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Hou YX, Ren W, He QQ, Huang LY, Gao TH, Li H. Tetramethylpyrazine induces reactive oxygen species-based mitochondria-mediated apoptosis in colon cancer cells. World J Gastrointest Oncol 2025; 17:104922. [DOI: 10.4251/wjgo.v17.i4.104922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer is one of the most common malignancies worldwide, and chemotherapy is a widely used strategy in colon cancer clinical therapy. Chemotherapy resistance is the main cause of recurrence and progression in colon cancer. Thus, novel drugs for treatment are urgently needed. Tetramethylpyrazine (TMP), a component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in tumors.
AIM To investigate the potential anticancer activity of TMP in colon cancer and the underlying mechanisms.
METHODS Colon cancer cells were incubated with different concentrations of TMP. Cell viability was evaluated by crystal violet staining assay, and cell apoptosis was assessed by flow cytometry. Apoptosis-associated protein expression was measured using Western blot analysis. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometry using DCF fluorescence intensity. Xenografts were established by the subcutaneous injection of colon cancer cells into nude mice; tumor growth was monitored and intracellular ROS was detected in tumors by malondialdehyde assay.
RESULTS TMP induced apoptosis of colon cancer cells via the activation of the mitochondrial pathway. TMP increased the generation of intracellular ROS and triggered mitochondria-mediated apoptosis in a caspase-dependent manner.
CONCLUSION Our study demonstrates that TMP induces the apoptosis of colon cancer cells and increases the generation of intracellular ROS. TMP triggers mitochondria-mediated apoptosis in a caspase-dependent manner. The accumulation of intracellular ROS is involved in TMP-induced apoptosis. Our findings suggest that TMP may be a potential therapeutic drug for the treatment of colon cancer.
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Affiliation(s)
- Yan-Xu Hou
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Wei Ren
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Qing-Qiang He
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Li-Yan Huang
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Tian-Hua Gao
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Hua Li
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
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Shahzad M, Hameed H, Amjad A, Khan MA, Qureshi IS, Hameed A, Saeed A, Munir R. An updated landscape on nanopharmaceutical delivery for mitigation of colon cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:2107-2125. [PMID: 39361171 DOI: 10.1007/s00210-024-03482-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 09/21/2024] [Indexed: 03/19/2025]
Abstract
Globally, colorectal cancer (CRC) continues to rank among the leading causes of cancer-related death. Systemic toxicity, multidrug resistance, and nonspecific targeting often pose challenges to conventional therapy for CRC. Because it is a complex disease with a complex genetic and environmental pathophysiology, advanced therapeutic strategies are needed. Nanotechnology presents a potential solution that may maximize therapeutic efficacy while minimizing negative effects by enabling personalized delivery of anticancer drugs. This review focuses on recent developments in colorectal drug delivery systems based on nanotechnology. Numerous nanomaterials, including liposomes, dendrimers, micelles, exosomes, and gold nanoparticles, are developed and used. Distinctive characteristics of mentioned nanocarriers are discussed along with strategies that can be employed for enhancing the delivery of drugs to colorectal cancer cells. The review also quotes the most relevant preclinical and clinical studies that show how these nanomaterials improve drug solubility, stability, and targeted delivery while overcoming the shortcomings of conventional therapies. Nanotechnology has made CRC treatment very efficient and advanced, which has opened up new possibilities for targeted drug delivery. Preclinical and clinical studies have also proved that the use of nano-formulations in colon-specific delivery systems have significant results, indicating potential for better patient outcomes. Future research can be done in order to overcome the hurdles regarding biocompatibility, expansion, and regulatory challenges. Large-scale clinical trials and nanomaterial formulation optimization should be the main goals of future research to confirm the efficacy and safety of these novel treatments.
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Affiliation(s)
- Maria Shahzad
- Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore, 54000, Pakistan
| | - Huma Hameed
- Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore, 54000, Pakistan.
| | - Ayesha Amjad
- Faculty of Food Technology and Nutrition Sciences, Lahore University of Biological and Applied Sciences, Lahore, 54000, Pakistan
| | - Mahtab Ahmad Khan
- Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore, 54000, Pakistan
| | - Inaba Shujaat Qureshi
- Department of Human Nutrition and Dietetics, Faculty of Rehabilitation and Allied Health Sciences, Riphah International University, Gulberg III, Lahore, 54000, Pakistan
| | - Anam Hameed
- Department of Human Nutrition and Dietetics, Faculty of Rehabilitation and Allied Health Sciences, Riphah International University, Gulberg III, Lahore, 54000, Pakistan
| | - Asad Saeed
- Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore, 54000, Pakistan
| | - Rabia Munir
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan
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Teng X, Wu B, Liang Z, Zhang L, Yang M, Liu Z, Liang Q, Wang C. Three bioactive compounds from Huangqin decoction ameliorate Irinotecan-induced diarrhea via dual-targeting of Escherichia coli and bacterial β-glucuronidase. Cell Biol Toxicol 2024; 40:88. [PMID: 39422738 PMCID: PMC11489186 DOI: 10.1007/s10565-024-09922-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024]
Abstract
Irinotecan (CPT-11) is a commonly prescribed chemotherapeutic for the treatment of colon cancer. Unfortunately, acute and delayed diarrhea are prominent side effects of CPT-11 use, and this limits its therapeutic potential. The curative effect of Huangqin decoction (HQD) on chemotherapy-induced diarrhea has been proven. This study investigated the efficacy of the components of HQD (baicalein, baicalin, and paeoniflorin) on CPT-11-induced diarrhea and their underlying mechanisms. Baicalein was found to be the most effective component in improving CPT-11-induced enterotoxicity by intestinal permeability test, ELISA, fluorescence co-localization, and IHC. The combination of baicalin, baicalin and paeoniflorin can obtain similar therapeutic effect to that of HQD. Mendelian randomization analysis, 16 s rRNA sequencing, and fluorescence imaging revealed that baicalein and baicalin significantly inhibited β-glucuronidase (β-GUS) activity. Bacterial abundance analysis and scanning electron microscopy showed that baicalein inhibited the proliferation of Escherichia coli by destroying its cell wall. The molecular dynamics and site-directed mutagenesis results revealed the structural basis for the inhibition of β-GUS by baicalein and baicalin. The results above provide a new idea for the development of drug therapy for adjuvant chemotherapy and theoretical guidance for the optimization of molecular structure targeting β-GUS.
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Affiliation(s)
- Xiaojun Teng
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bingxin Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zuhui Liang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lisheng Zhang
- Research Center of Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Maolin Yang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongqiu Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
- Acupuncture Building, Guangdong Province, Guangzhou University of Chinese Medicine, Xiaoguwei Street, Panyu District, Guangzhou City, 510006, China.
| | - Qi Liang
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 51800, People's Republic of China.
- Acupuncture Building, Guangdong Province, Guangzhou University of Chinese Medicine, Xiaoguwei Street, Panyu District, Guangzhou City, 510006, China.
| | - Caiyan Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
- Acupuncture Building, Guangdong Province, Guangzhou University of Chinese Medicine, Xiaoguwei Street, Panyu District, Guangzhou City, 510006, China.
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Ju F, Chen K, Yin D. Clinical effect analysis of different regimens of capecitabine in the treatment of patients with advanced colon cancer. J Chemother 2024:1-10. [PMID: 39132982 DOI: 10.1080/1120009x.2024.2385254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 07/10/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
To assess the efficacy and safety of capecitabine in treating advanced colon cancer. Patients with advanced colon cancer were randomized into three groups: control group (n = 50, daily dose 2,500 mg/m2), the medium-dose group (n = 50, daily dose 2,000 mg/m2), and the low-dose group (n = 50, daily dose 1,500 mg/m2) capecitabine for 4 cycles(12 weeks). Afterwards, the response rate, quality of life, and adverse reactions of the three groups were collected for comparison. Efficacy rates were 50%, 70%, and 72%, respectively, with the low-dose group showing the highest efficacy (χ2 = 6.424, p = 0.040); Quality of life comparison results indicated significant differences in physical function (F = 98.528, p < 0.001), role function (F = 123.418, p < 0.001), social function(F = 89.539, p < 0.001), emotional function (6 F = 77.295, p < 0.001), cognitive function (F = 83.529, p < 0.001), and overall quality of life (F = 99.528, p < 0.001) among the three groups, and the three groups returned consistent scores, with the low-dose group scoring highest. Incidence rates were 86.00%, 46.00%, 34.00%, with the control group having the highest rate (χ2 = 16.505, p < 0.001). Capecitabine at a dosage of 1,500 mg/m2 demonstrated a good therapeutic effect and improved the quality of life in patients with advanced colon cancer, with a lower incidence of adverse reactions. A prolonged treatment cycle with reduced dosage is suggested to further improve treatment outcomes and patient prognosis. Trial registration The study was registered on clicaltrials.gov 'NCT06246461' on 30/01/2024.
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Affiliation(s)
- Feng Ju
- Department of Pharmacy Management, Jingjiang People's Hospital, Jingjiang, China
| | - Kaixia Chen
- Department of Pharmacy Management, Jingjiang People's Hospital, Jingjiang, China
| | - Dengyang Yin
- Clinical Pharmacy Support, Jingjiang People's Hospital, Jingjiang, China
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Li Y, Ran D, Basnet S, Zhang B, Pei H, Dan C, Zhang Z, Zhang L, Lu T, Peng Y, Du C. The expression and clinical significance of CFAP65 in colon cancer. BMC Gastroenterol 2024; 24:222. [PMID: 38992586 PMCID: PMC11238475 DOI: 10.1186/s12876-024-03317-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 07/04/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND CFAP65 (cilia and flagella associated protein 65) is a fundamental protein in the development and formation of ciliated flagella, but few studies have focused on its role in cancer. This study aimed to investigate the prognostic significance of CFAP65 in colon cancer. METHODS The functionally enriched genes related to CFAP65 were analyzed through the Gene Ontology (GO) database. Subsequently, CFAP65 expression levels in colon cancer were evaluated by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) and immunoblotting in 20 pairs of frozen samples, including tumors and their matched paratumor tissue. Furthermore, protein expression of CFAP65 in 189 colon cancer patients were assessed via immunohistochemical staining. The correlations between CFAP65 expression and clinical features as well as long-term survival were statistically analyzed. RESULTS CFAP65-related genes are significantly enriched on cellular processes of cell motility, ion channels, and GTPase-associated signaling. The expression of CFAP65 was significantly higher in colon cancer tissue compared to paratumor tissue. The proportion of high expression and low expression of CFAP65 in the clinical samples of colon cancer were 61.9% and 38.1%, respectively, and its expression level was not associated with the clinical parameters including gender, age, tumor location, histological differentiation, tumor stage, vascular invasion and mismatch repair deficiency. The five-year disease-free survival rate of the patients with CFAP65 low expression tumors was significantly lower than that those with high expression tumors (56.9% vs. 72.6%, P = 0.03), but the overall survival rate has no significant difference (69% vs. 78.6%, P = 0.171). The cox hazard regression analysis model showed that CFAP65 expression, tumor stage and tumor location were independent prognostic factors. CONCLUSIONS In conclusion, we demonstrate CFAP65 is a potential predictive marker for tumor progression in colon cancer.
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Affiliation(s)
- Yunze Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China
| | - Dongmei Ran
- Department of Pathology, Southern University of Science and Technology Hospital, Shenzhen, 518055, Guangdong, China
- Digestive Tumor Center, Southern University of Science and Technology Hospital, Shenzhen, 518055, Guangdong, China
| | - Shiva Basnet
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China
| | - Buzhe Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China
| | - Hongjing Pei
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China
| | - Chenchen Dan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China
| | - Zixuan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China
| | - Liang Zhang
- Department of Gastroenterology, Southern University of Science and Technology Hospital, Shenzhen, 518055, Guangdong, China
| | - Tianyu Lu
- Department of Gastroenterology, Southern University of Science and Technology Hospital, Shenzhen, 518055, Guangdong, China
| | - Yifan Peng
- Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, 100142, P.R. China.
| | - Changzheng Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, P.R. China.
- Digestive Tumor Center, Southern University of Science and Technology Hospital, Shenzhen, 518055, Guangdong, China.
- Beijing Tsinghua Changgung Hospital & Tsinghua University School of Medicine, 168 Litang Road, Changping District, Beijing, 102218, P.R. China.
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Chawrylak K, Leśniewska M, Mielniczek K, Sędłak K, Pelc Z, Pawlik TM, Polkowski WP, Rawicz-Pruszyński K. Gut Microbiota-Adversary or Ally? Its Role and Significance in Colorectal Cancer Pathogenesis, Progression, and Treatment. Cancers (Basel) 2024; 16:2236. [PMID: 38927941 PMCID: PMC11201452 DOI: 10.3390/cancers16122236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/24/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
In 2022, colorectal cancer (CRC) was the third most prevalent malignancy worldwide. The therapeutic approach for CRC typically involves a multimodal regimen. The human gut microbiota comprises over 35,000 bacterial species. The composition of the gut microbiota is influenced by dietary intake, which plays a crucial role in food absorption, nutrient extraction, and the development of low-grade inflammation. Dysbiosis in the gut microbiota is a key driver of inflammation and is strongly associated with CRC development. While the gut microbiome influences CRC initiation and progression, emerging evidence suggests a role for the gut microbiome in modulating the efficacy and toxicity of cancer treatments. Therapeutic strategies targeting the gut microbiome, such as probiotics, hold promise as effective interventions in the modern therapeutical approach to CRC. For example, Microbiota Implementation to Reduce Anastomotic Colorectal Leaks (MIRACLe) implementation has resulted in improvements in clinical outcomes, including reduced incidence of anastomotic leakage (AL), surgical site infections (SSIs), reoperation, as well as shorter recovery times and hospital stays compared with the control group. Therefore, this review aims to describe the current state of knowledge regarding the involvement of the gut microbiota in CRC pathogenesis and its potential therapeutic implications to treat CRC.
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Affiliation(s)
- Katarzyna Chawrylak
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
| | - Magdalena Leśniewska
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
| | - Katarzyna Mielniczek
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
| | - Katarzyna Sędłak
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
| | - Zuzanna Pelc
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA;
| | - Wojciech P. Polkowski
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
| | - Karol Rawicz-Pruszyński
- Department of Surgical Oncology, Medical University of Lublin, Radziwiłłowska 13 St., 20-080 Lublin, Poland; (K.C.); (M.L.); (K.S.); (Z.P.); (W.P.P.); (K.R.-P.)
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Sun M, Zhan H, Long X, Alsayed AM, Wang Z, Meng F, Wang G, Mao J, Liao Z, Chen M. Dehydrocostus lactone alleviates irinotecan-induced intestinal mucositis by blocking TLR4/MD2 complex formation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155371. [PMID: 38518649 DOI: 10.1016/j.phymed.2024.155371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/08/2024] [Accepted: 01/15/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. PURPOSE The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. METHODS The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo. And DHL on reducing inflammatory response and regulating TLR4/NF-κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. RESULTS DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. CONCLUSION This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11.
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Affiliation(s)
- Miaomiao Sun
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Honghong Zhan
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Xiaoliang Long
- School of Life Sciences, Integrative Science Center of Germplasm Creation in Western China (Chongqing) Science City and Southwest University, TAAHC-SWU Medicinal Plant Joint R&D Centre, Southwest University, Chongqing 400715, China
| | - Ali M Alsayed
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Zhe Wang
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Fancheng Meng
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Guowei Wang
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Jingxin Mao
- Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Zhihua Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Min Chen
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.
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Feng Y, Lu J, Jiang J, Wang M, Guo K, Lin S. Berberine: Potential preventive and therapeutic strategies for human colorectal cancer. Cell Biochem Funct 2024; 42:e4033. [PMID: 38742849 DOI: 10.1002/cbf.4033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/28/2024] [Accepted: 04/28/2024] [Indexed: 05/16/2024]
Abstract
Colorectal cancer (CRC) is a common digestive tract tumor, with incidences continuing to rise. Although modern medicine has extended the survival time of CRC patients, its adverse effects and the financial burden cannot be ignored. CRC is a multi-step process and can be caused by the disturbance of gut microbiome and chronic inflammation's stimulation. Additionally, the presence of precancerous lesions is also a risk factor for CRC. Consequently, scientists are increasingly interested in identifying multi-target, safe, and economical herbal medicine and natural products. This paper summarizes berberine's (BBR) regulatory mechanisms in the occurrence and development of CRC. The findings indicate that BBR regulates gut microbiome homeostasis and controls mucosal inflammation to prevent CRC. In the CRC stage, BBR inhibits cell proliferation, invasion, and metastasis, blocks the cell cycle, induces cell apoptosis, regulates cell metabolism, inhibits angiogenesis, and enhances chemosensitivity. BBR plays a role in the overall management of CRC. Therefore, using BBR as an adjunct to CRC prevention and treatment could become a future trend in oncology.
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Affiliation(s)
- Yuqian Feng
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiamin Lu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jing Jiang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Menglei Wang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Kaibo Guo
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China
| | - Shengyou Lin
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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Kuang Z, Wang J, Liu K, Wu J, Li J. Optimal duration of oxaliplatin-based adjuvant chemotherapy in patients with different risk factors for stage II-III colon cancer: a meta-analysis. Int J Surg 2024; 110:3030-3038. [PMID: 38349218 PMCID: PMC11093490 DOI: 10.1097/js9.0000000000001175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/29/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND The duration of oxaliplatin-based chemotherapy in high-risk stage II, low-risk stage III, and high-risk stage III colon cancer (CC) patients is controversial. To reduce the risk of adverse events (AEs) without compromising efficacy while improving chemotherapy compliance is crucial. METHODS The authors searched Cochrane, Embase, Pubmed, and Web of Science databases for articles from inception to August 8, 2023, the main outcomes were disease-free survival, overall survival, chemotherapy completion rates, and AE frequency. RESULTS Six randomized controlled trials (RCTs) involving 10 332 patients were included. Disease-free survival analysis revealed that only the high-risk stage III CC patients experienced better results with the 6-month FOLFOX regimen when compared with the 3-month regimen [Hazard ratio (HR): 1.32, 95% CI: 1.15-1.51, P <0.0001). Overall survival (OS) analysis revealed that extending the use of FOLFOX and CAPEOX regimens did not provide survival benefits for stage III CC patients (HR: 1.16, 95% CI: 0.9-1.49, and HR: 0.89, 95% CI: 0.67-1.18, P =0.40). The completion rate of the 3-month oxaliplatin-based adjuvant chemotherapy regimen was significantly higher than that of the 6-month regimen [Relative risk (RR): 1.16, 95% CI: 1.06-1.27, P =0.002]. Moreover, the 3-month regimen had significantly lower AE rates than the 6-month regimen (RR: 0.62, 95% CI: 0.57-0.68, P <0.00001), with differences mainly concentrated in grade 3/4 neutropenia (RR: 0.70, 95% CI: 0.59-0.85, P =0.0002), peripheral sensory neuropathy at ≥grade 2 (RR: 0.45, 95% CI: 0.38-0.53, P <0.00001), and hand-foot syndrome at ≥grade 2 (RR: 0.36, 95% CI: 0.17-0.77, P =0.009). CONCLUSION The 6-month FOLFOX regimen should only be recommended for high-risk stage III CC, while the 3-month regimen can be recommended for other stages. A 3-month CAPEOX regimen can be recommended for stage II-III CC.
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Affiliation(s)
- Ziyu Kuang
- Guang’anmen Hospital of China Academy of Chinese Medical Sciences
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Jiaxi Wang
- Guang’anmen Hospital of China Academy of Chinese Medical Sciences
| | - Kexin Liu
- Guang’anmen Hospital of China Academy of Chinese Medical Sciences
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Jingyuan Wu
- Guang’anmen Hospital of China Academy of Chinese Medical Sciences
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Jie Li
- Guang’anmen Hospital of China Academy of Chinese Medical Sciences
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10
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Wang Y, Xu M, Yao Y, Li Y, Zhang S, Fu Y, Wang X. Extracellular cancer‑associated fibroblasts: A novel subgroup in the cervical cancer microenvironment that exhibits tumor‑promoting roles and prognosis biomarker functions. Oncol Lett 2024; 27:167. [PMID: 38449793 PMCID: PMC10915806 DOI: 10.3892/ol.2024.14300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 01/10/2024] [Indexed: 03/08/2024] Open
Abstract
Tumor invasion and metastasis are the processes that primarily cause adverse outcomes in patients with cervical cancer. Cancer-associated fibroblasts (CAFs), which participate in cancer progression and metastasis, are novel targets for the treatment of tumors. The present study aimed to assess the heterogeneity of CAFs in the cervical cancer microenvironment through single-cell RNA sequencing. After collecting five cervical cancer samples and obtaining the CAF-associated gene sets, the CAFs in the cervical cancer microenvironment were divided into myofibroblastic CAFs and extracellular (ec)CAFs. The ecCAFs appeared with more robust pro-tumorigenic effects than myCAFs according to enrichment analysis. Subsequently, through combining the ecCAF hub genes and bulk gene expression data for cervical cancer obtained from The Cancer Genome Atlas and Gene Ontology databases, univariate Cox regression and least absolute shrinkage and selection operator analyses were performed to establish a CAF-associated risk signature for patients with cancer. The established risk signature demonstrated a stable and strong prognostic capability in both the training and validation cohorts. Subsequently, the association between the risk signature and clinical data was evaluated, and a nomogram to facilitate clinical application was established. The risk score was demonstrated to be associated with both the tumor immune microenvironment and the therapeutic responses. Moreover, the signature also has predictive value for the prognosis of head and neck squamous cell carcinoma, and bladder urothelial carcinoma, which were also associated with human papillomavirus infection. In conclusion, the present study assessed the heterogeneity of CAFs in the cervical cancer microenvironment, and a subgroup of CAFs that may be closely associated with tumor progression was defined. Moreover, a signature based on the hub genes of ecCAFs was shown to have biomarker functionality in terms of predicting survival rates, and therefore this CAF subgroup may become a therapeutic target for cervical cancer in the future.
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Affiliation(s)
- Yuehan Wang
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Mingxia Xu
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yeli Yao
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Ying Li
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Songfa Zhang
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yunfeng Fu
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xinyu Wang
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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11
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Gao Z, Wan Z, Yu P, Shang Y, Zhu G, Jiang H, Chen Y, Wang S, Lei F, Huang W, Zeng Q, Wang Y, Rong W, Hong Y, Gao Q, Niu P, Zhai Z, An K, Ding C, Wang Y, Gu G, Wang X, Meng Q, Ye S, Liu H, Gu J. A recurrence-predictive model based on eight genes and tumor mutational burden/microsatellite instability status in Stage II/III colorectal cancer. Cancer Med 2024; 13:e6720. [PMID: 38111983 PMCID: PMC10807589 DOI: 10.1002/cam4.6720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/18/2023] [Accepted: 10/27/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Although adjuvant chemotherapy (ACT) is widely used to treat patients with Stage II/III colorectal cancer (CRC), administering ACT to specific patients remains a challenge. The decision to ACT requires an accurate assessment of recurrence risk and absolute treatment benefit. However, the traditional TNM staging system does not accurately assess a patient's individual risk of recurrence. METHODS To identify recurrence risk-related genetic factors for Stage II/III CRC patients after radical surgery, we conducted an analysis of whole-exome sequencing of 47 patients with Stage II/III CRC who underwent radical surgery at five institutions. Patients were grouped into non-recurrence group (NR, n = 24, recurrence-free survival [RFS] > 5 years) and recurrence group (R, n = 23, RFS <2 years). The TCGA-COAD/READ cohort was employed as the validation dataset. RESULTS A recurrence-predictive model (G8plus score) based on eight gene (CUL9, PCDHA12, HECTD3, DCX, SMARCA2, FAM193A, AATK, and SORCS2) mutations and tumor mutation burden/microsatellite instability (TMB/MSI) status was constructed, with 97.87% accuracy in our data and 100% negative predictive value in the TCGA-COAD/READ cohort. For the TCGA-COAD/READ cohort, the G8plus-high group had better RFS (HR = 0.22, p = 0.024); the G8plus-high tumors had significantly more infiltrated immune cell types, higher tertiary lymphoid structure signature scores, and higher immunological signature scores. The G8plus score was also a predict biomarker for immunotherapeutic in advanced CRC in the PUCH cohort. CONCLUSIONS In conclusion, the G8plus score is a powerful biomarker for predicting the risk of recurrence in patients with stage II/III CRC. It can be used to stratify patients who benefit from ACT and immunotherapy.
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Affiliation(s)
- Zhaoya Gao
- Department of General SurgeryPeking University First HospitalBeijingChina
| | - Zhiyi Wan
- Genecast Biotechnology Co., Ltd.Wuxi CityJiangsu ProvinceChina
| | - Pengfei Yu
- Department of General SurgeryAir Force Medical Center, Chinese People's Liberation ArmyBeijingChina
| | - Yan Shang
- Department of Colorectal SurgeryCancer Hospital of China Medical University, Liaoning Cancer Hospital and InstituteShenyangLiaoning ProvinceChina
| | - Guangsheng Zhu
- Department of Gastrointestinal SurgeryHubei Cancer HospitalWuhanHubei ProvinceChina
| | - Huiyuan Jiang
- Department of Colorectal and Anal SurgeryShanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Yawei Chen
- Genecast Biotechnology Co., Ltd.Wuxi CityJiangsu ProvinceChina
| | - Shengzhou Wang
- Genecast Biotechnology Co., Ltd.Wuxi CityJiangsu ProvinceChina
| | - Fuming Lei
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Wensheng Huang
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Qingmin Zeng
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Yanzhao Wang
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Wanshui Rong
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Yuming Hong
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Qingkun Gao
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Pengfei Niu
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Zhichao Zhai
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Ke An
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Changmin Ding
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
| | - Yunfan Wang
- Department of PathologyPeking University Shougang HospitalBeijingChina
| | - Guoli Gu
- Department of General SurgeryAir Force Medical Center, Chinese People's Liberation ArmyBeijingChina
| | - Xin Wang
- Department of General SurgeryPeking University First HospitalBeijingChina
| | - Qingkai Meng
- Department of Colorectal SurgeryCancer Hospital of China Medical University, Liaoning Cancer Hospital and InstituteShenyangLiaoning ProvinceChina
| | - Shengwei Ye
- Department of Gastrointestinal SurgeryHubei Cancer HospitalWuhanHubei ProvinceChina
| | - Haiyi Liu
- Department of Colorectal and Anal SurgeryShanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Jin Gu
- Department of Gastrointestinal SurgeryPeking University Shougang HospitalBeijingChina
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal SurgeryPeking University Cancer Hospital & InstituteBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- Peking University International Cancer InstituteBeijingChina
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12
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Cura Y, Sánchez-Martín A, Márquez-Pete N, González-Flores E, Martínez-Martínez F, Pérez-Ramírez C, Jiménez-Morales A. Role of Single-Nucleotide Polymorphisms in Genes Implicated in Capecitabine Pharmacodynamics on the Effectiveness of Adjuvant Therapy in Colorectal Cancer. Int J Mol Sci 2023; 25:104. [PMID: 38203276 PMCID: PMC10778960 DOI: 10.3390/ijms25010104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/08/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Colorectal cancer (CRC) is a highly prevalent form of neoplasm worldwide. Capecitabine, an oral antimetabolite, is widely used for CRC treatment; however, there exists substantial variation in individual therapy response. This may be due to genetic variations in genes involved in capecitabine pharmacodynamics (PD). In this study, we investigated the role of single-nucleotide polymorphisms (SNPs) related to capecitabine's PD on disease-free survival (DFS) in CRC patients under adjuvant treatment. Thirteen SNPs in the TYMS, ENOSF1, MTHFR, ERCC1/2, and XRCC1/3 genes were genotyped in 142 CRC patients using real-time PCR with predesigned TaqMan® probes. A significant association was found between favorable DFS and the ENOSF1 rs2612091-T allele (p = 0.010; HR = 0.34; 95% CI = 0.14-0.83), as well as with the TYMS/ENOSF1 region ACT haplotype (p = 0.012; HR = 0.37; 95% CI = 0.17-0.80). Other factors such as low histological grade (p = 0.009; HR = 0.34; 95% CI = 0.14-0.79) and a family history of cancer (p = 0.040; HR = 0.48; 95% CI = 0.23-0.99) were also linked to improved DFS. Therefore, the SNP ENOSF1 rs2612091 could be considered as a predictive genetic biomarker for survival in CRC patients receiving capecitabine-based adjuvant regimens.
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Affiliation(s)
- Yasmin Cura
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (Y.C.)
| | - Almudena Sánchez-Martín
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (Y.C.)
| | - Noelia Márquez-Pete
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (Y.C.)
| | - Encarnación González-Flores
- Medical Oncology, University Hospital Virgen de las Nieves, 18014 Granada, Spain
- Biomedical Research Institute—ibs.Granada, 18012 Granada, Spain
| | | | - Cristina Pérez-Ramírez
- Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, 18016 Granada, Spain
| | - Alberto Jiménez-Morales
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (Y.C.)
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13
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Singh I, Das R, Kumar A. Network pharmacology-based anti-colorectal cancer activity of piperlonguminine in the ethanolic root extract of Piper longum L. Med Oncol 2023; 40:320. [PMID: 37796360 DOI: 10.1007/s12032-023-02185-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/04/2023] [Indexed: 10/06/2023]
Abstract
Colorectal cancer (CRC) has the second highest incidence and fatality rates of any malignancy, at 10.2 and 9.2%, respectively. Plants and plants-based products for thousands of years have been utilized to treat cancer along with other associated health issues. Alkaloids are a valuable class of chemical compounds with great potential as new medicine possibilities. Piper longum Linn contains various types of alkaloids. In this research, the ethanolic root extract of P. longum (EREPL) is the subject of study based on network pharmacology. Two alkaloids were chosen from the gas chromatography mass spectrometry (GC-MS) analysis. However, only piperlonguminine received preference because it adhered to Lipinski's rule and depicted no toxicity. Web tools which are available online, like, Swiss ADME, pkCSMand ProTox-II were used to evaluate the pharmacokinetics and physiochemical properties of piperlonguminine. The database that SwissTargetPrediction and TCMSP maintain contains the targets for piperlonguminine. Using DisGeNET, GeneCards and Open Targets Platform databases, we were able to identify targets of CRC. The top four hub genes identified by Cytoscape are SRC, MTOR, EZH2, and MAPK3. The participation of hub genes in colorectal cancer-related pathways was examined using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) database. The colorectal cancer pathway, the ErbB signaling pathway and the mTOR signaling pathway emerged to be important. Our findings show that the hub genes are involved in the aforementioned pathways for tumor growth, which calls for their downregulation. Additionally, piperlonguminine has the potential to become a successful medicine in the future for the treatment of CRC.
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Affiliation(s)
- Indrajeet Singh
- Department of Biotechnology, Faculty of Engineering and Technology, Rama University, G.T. Road, Mandhana, Kanpur, Uttar Pradesh, 209217, India
| | - Richa Das
- Department of Biotechnology, Parul Institute of Applied Science, Parul University, Vadodara, Gujarat, 391760, India
| | - Ajay Kumar
- Department of Biotechnology, Faculty of Engineering and Technology, Rama University, G.T. Road, Mandhana, Kanpur, Uttar Pradesh, 209217, India.
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14
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Ma Y, Lai X, Wen Z, Zhou Z, Yang M, Chen Q, Wang X, Mei F, Yang L, Yin T, Sun S, Lu G, Qi J, Lin H, Han H, Yang Y. Design, synthesis and biological evaluation of novel modified dual-target shikonin derivatives for colorectal cancer treatment. Bioorg Chem 2023; 139:106703. [PMID: 37399615 DOI: 10.1016/j.bioorg.2023.106703] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/15/2023] [Accepted: 06/25/2023] [Indexed: 07/05/2023]
Abstract
Warburg effect provides energy and material essential for tumor proliferation, the reverse of Warburg effect provides insights into the development of a novel anti-cancer strategy. Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only contribute to the Warburg effect through accelerating aerobic glycolysis, but also serve as druggable target for colorectal cancer (CRC). Considering that targeting PKM2 or PDK1 alone does not seem to be sufficient to remodel abnormal glucose metabolism and achieve significant antitumor activity, a series of novel benzenesulfonyl shikonin derivatives were designed to regulate PKM2 and PDK1 simultaneously. By means of molecular docking and antiproliferative screen, we found that compound Z10 could act as the combination of PKM2 activator and PDK1 inhibitor, thereby significantly inhibited glycolysis that reshaping tumor metabolism. Moreover, Z10 could inhibit proliferation, migration and induce apoptosis in CRC cell HCT-8. Finally, the in vivo anti-tumor activity of Z10 was evaluated in a colorectal cancer cell xenograft model in nude mice and the results demonstrated that Z10 induced tumor cell apoptosis and inhibited tumor cell proliferation with lower toxicity than shikonin. Our findings indicated that it is feasible to alter tumor energy metabolism through multi-target synergies, and the dual-target benzenesulfonyl shikonin derivative Z10 could be a potential anti-CRC agent.
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Affiliation(s)
- Yudi Ma
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Xiaohui Lai
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; School of Biology and Geography Science, Yili Normal University, Yining 835000, China
| | - Zhongling Wen
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Ziling Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Minkai Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Qingqing Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Xuan Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Feng Mei
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Liu Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Tongming Yin
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Shucun Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Guihua Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Jinliang Qi
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Hongyan Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China; School of Pharmacy, Changzhou University, Changzhou 213164, China.
| | - Hongwei Han
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
| | - Yonghua Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
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15
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Crook CJ, Li D. Adjuvant and Neoadjuvant Treatments for Resectable Hepatocellular Carcinoma. Curr Oncol Rep 2023; 25:1191-1201. [PMID: 37688739 PMCID: PMC10556166 DOI: 10.1007/s11912-023-01455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE OF REVIEW This review provides an update on the developments of adjuvant and neoadjuvant liver-directed and systemic therapy options for patients with resectable hepatocellular carcinoma. RECENT FINDINGS Data on liver-directed treatment in the adjuvant and neoadjuvant settings are sparse and results are conflicting; many studies suggest that optimizing patient selection criteria is a key milestone required to improve study design and clinical benefit to patients. Systemic treatment options are primarily focused on investigation of anti-PD-1/L1 immunotherapeutic agents, either alone or in combination with other drugs. Numerous clinical trials in both adjuvant and neoadjuvant settings are in progress. Exploration of liver-directed and systemic treatment options for adjuvant and neoadjuvant treatment of patients with resectable hepatocellular carcinoma has the potential to improve clinical outcomes for this patient population.
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Affiliation(s)
- Christiana J Crook
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Road, Duarte, CA, 91010, USA
| | - Daneng Li
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Road, Duarte, CA, 91010, USA.
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16
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Shi W, Chen J, Yao N, Wu T, Suo X, Wang Q, Liu J, Yu G, Zhang K. The prognostic ability of radiotherapy of different colorectal cancer histological subtypes and tumor sites. Sci Rep 2023; 13:11758. [PMID: 37474552 PMCID: PMC10359278 DOI: 10.1038/s41598-023-38853-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 07/16/2023] [Indexed: 07/22/2023] Open
Abstract
The prognostic significance of radiotherapy (RT) for colorectal cancer (CRC) has shown conflicting results, particularly among different pathological subtypes, including adenocarcinoma (AC), mucinous adenocarcinoma (MC), and signet-ring cell carcinoma (SR). This study analyzed the prognosis of three pathological CRC types and focused on the prognostic significance of RT on three CRC histological subtypes. Patients diagnosed with AC (n = 54,174), MC (n = 3813), and SR (n = 664) in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database (2010-2017) were evaluated. Cox regression models and competitive risk models were built to assess the effect of RT on the risk of CRC-associated death. Potential interactions between RT and stratified variables including age, sex, and tumor location were examined by multiplicative models. Compared with AC patients, SR patients had the worst overall survival (OS) among 3 subtypes of CRC (log-rank test, p < 0.001). Compared with patients who did not receive radiotherapy, RT was associated with a 1.09-fold (HR = 1.09, 95%[CI]: 1.03, 1.15) elevated risk of death among AC patients. In the SR group, RT significantly reduced the risk of death by 39% (HR = 0.61, 95%[CI]: 0.39-0.95). However, RT did not appear to independently influence survival in the MC group (HR = 0.96, 95%[CI]: 0.77, 1.21). In the subgroup analysis, tumor location (colon and rectum) significantly modified the association between RT and the risk of death among the AC and SR patients (p for interaction < 0.05). SR patients exhibited a worse OS (overall survival) than AC patients, and the effect of RT varied according to CRC histological subtypes. This can ultimately lead to more personalized and effective treatment strategies for CRC patients.
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Affiliation(s)
- Wenzai Shi
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Jianfei Chen
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing, 100038, China
- School of Oncology, Capital Medical University, Beijing, 100038, China
| | - Nan Yao
- Department of General Surgery, Aerospace Center Hospital, Beijing, 100089, China
| | - Tiantian Wu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Xiaopeng Suo
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Jun Liu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Guoyong Yu
- Department of Nephrology, Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, East 4th North Street 279, Dongcheng District, Beijing, 100007, China.
| | - Keming Zhang
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China.
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17
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Li C, Zhang K, Gong Y, Wu Q, Zhang Y, Dong Y, Li D, Wang Z. Based on cuproptosis-related lncRNAs, a novel prognostic signature for colon adenocarcinoma prognosis, immunotherapy, and chemotherapy response. Front Pharmacol 2023; 14:1200054. [PMID: 37377924 PMCID: PMC10291194 DOI: 10.3389/fphar.2023.1200054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Introduction: Colon adenocarcinoma (COAD) is a special pathological subtype of colorectal cancer (CRC) with highly heterogeneous solid tumors with poor prognosis, and novel biomarkers are urgently required to guide its prognosis. Material and methods: RNA-Seq data of COAD were downloaded through The Cancer Genome Atlas (TCGA) database to determine cuproptosis-related lncRNAs (CRLs) using weighted gene co-expression network analysis (WGCNA). The scores of the pathways were calculated by single-sample gene set enrichment analysis (ssGSEA). CRLs that affected prognoses were determined via the univariate COX regression analysis to develop a prognostic model using multivariate COX regression analysis and LASSO regression analysis. The model was assessed by applying Kaplan-Meier (K-M) survival analysis and receiver operating characteristic curves and validated in GSE39582 and GSE17538. The tumor microenvironment (TME), single nucleotide variants (SNV), and immunotherapy response/chemotherapy sensitivity were assessed in high- and low-score subgroups. Finally, the construction of a nomogram was adopted to predict survival rates of COAD patients during years 1, 3, and 5. Results: We found that a high cuproptosis score reduced the survival rates of COAD significantly. A total of five CRLs affecting prognosis were identified, containing AC008494.3, EIF3J-DT, AC016027.1, AL731533.2, and ZEB1-AS1. The ROC curve showed that RiskScore could perform well in predicting the prognosis of COAD. Meanwhile, we found that RiskScore showed good ability in assessing immunotherapy and chemotherapy sensitivity. Finally, the nomogram and decision curves showed that RiskScore would be a powerful predictor for COAD. Conclusion: A novel prognostic model was constructed using CRLs in COAD, and the CRLs in the model were probably a potential therapeutic target. Based on this study, RiskScore was an independent predictor factor, immunotherapy response, and chemotherapy sensitivity for COAD, providing a new scientific basis for COAD prognosis management.
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Affiliation(s)
- Chong Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, China
- Department of Oncology, Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Keqian Zhang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yuzhu Gong
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qinan Wu
- Endocrinology Department, Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Yanyan Zhang
- Department of Oncology, Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Dong
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Dejia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, China
| | - Zhe Wang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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18
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Shakerdi L, Ryan A. Drug-induced hyperammonaemia. J Clin Pathol 2023:jcp-2022-208644. [PMID: 37164630 DOI: 10.1136/jcp-2022-208644] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 04/28/2023] [Indexed: 05/12/2023]
Abstract
Hyperammonaemia (HA) as a consequence of numerous primary or secondary causes, gives rise to clinical manifestations due to its toxic effects on the brain. The neurological consequences broadly reflect the ammonia level, duration and age, with paediatric patients being more susceptible. Drug-induced HA may arise due to either decreased ammonia elimination or increased production. This is associated most frequently with use of valproate and presents a dilemma between ongoing therapeutic need, toxicity and the possibility of an alternative cause. As there is no specific test for drug-induced HA, prompt discussion with a metabolic physician is recommended, as the neurotoxic effects are time-dependent. Specific guidelines for managing drug-induced HA have yet to be published and hence the treatment approach outlined in this review reflects that outlined in relevant urea cycle disorder guidelines.
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Affiliation(s)
- Loai Shakerdi
- National Centre for Inherited Metabolic Disorders, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Aidan Ryan
- Chemical Pathology, Cork University Hospital Biochemistry Laboratory, Cork, Ireland
- Pathology, University College Cork College of Medicine and Health, Cork, Ireland
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19
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Zhang D, Fu Y, Liu Y, Wu Y, Chen J, Zhang L, Wang R, Chen Z, Liu T. 8-Methoxyflindersine-Induced Apoptosis and Cell Cycle Disorder Involving MAPK Signaling Activation in Human Colorectal Cancer Cells. Int J Mol Sci 2023; 24:ijms24098039. [PMID: 37175741 PMCID: PMC10179151 DOI: 10.3390/ijms24098039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors with a high lethal rate globally, and novel strategies for its prevention and therapy are urgently needed. In our previous work, 8-methoxyflindersine (8-MF), a quinoline alkaloid, was isolated from the Dictamni cortex, and its bioactivities were largely unknown. In this study, we found that 8-MF significantly inhibited cell viability in the CRC cell lines LoVo and RKO. The 8-MF-induced CRC cell apoptosis, as well as cell cycle disorder, were further verified by cyclins dysregulation in mRNA and protein levels. Further, the activation of MAPK family members p38 and ERK1/2 was observed after 8-MF treatment. Moreover, the protein-protein interaction of 8-MF with cyclins and MAPKs was demonstrated using the STRING database. The 8-MF could bind to p38 and ERK1/2 proteins in molecular docking. Taken together, we found that 8-MF induced apoptosis and cell cycle disorder involving MAPK signaling activation in CRC cells, indicating 8-MF as a novel lead compound candidate for the development of anti-tumor drugs for CRC.
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Affiliation(s)
- Dianbao Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Yunmei Fu
- Department of Natural Products Chemistry, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Ying Liu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Yifan Wu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Jiayu Chen
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Luting Zhang
- Department of Natural Products Chemistry, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Rui Wang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Zaixing Chen
- Central Laboratory, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Tao Liu
- Department of Natural Products Chemistry, School of Pharmacy, China Medical University, Shenyang 110122, China
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20
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Liu G, Chen J, Bao Z. Promising antitumor effects of the curcumin analog DMC-BH on colorectal cancer cells. Aging (Albany NY) 2023; 15:2221-2236. [PMID: 36971681 PMCID: PMC10085616 DOI: 10.18632/aging.204610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 03/04/2023] [Indexed: 04/07/2023]
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the digestive system worldwide. DMC-BH, a curcumin analog, has been reported to possess anticancer properties against human gliomas. However, its effects and mechanism on CRC cells are still unknown. Our present study demonstrated that DMC-BH had stronger cytostatic ability than curcumin against CRC cells in vitro and in vivo. It effectively inhibited the proliferation and invasion and promoted the apoptosis of HCT116 and HT-29 cells. RNA-Seq and data analysis indicated that its effects might be mediated by regulation of the PI3K/AKT signaling. Western blotting further confirmed that it dose-dependently suppressed the phosphorylation of PI3K, AKT and mTOR. The Akt pathway activator SC79 reversed the proapoptotic effects of DMC-BH on CRC cells, indicating that its effects are mediated by PI3K/AKT/mTOR signaling. Collectively, the results of the present study suggest that DMC-BH exerts more potent effects than curcumin against CRC by inactivating the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Gang Liu
- Department of General Surgery, Suzhou Medical College of Soochow University, Suzhou 215300, Jiangsu Province, China
- Department of General Surgery, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
| | - Jian Chen
- Department of General Surgery, Suzhou Medical College of Soochow University, Suzhou 215300, Jiangsu Province, China
- Department of General Surgery, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
| | - Zhicheng Bao
- Department of Rehabilitation, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou 215300, Jiangsu Province, China
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21
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High-Throughput Sequencing Reveals That Rotundine Inhibits Colorectal Cancer by Regulating Prognosis-Related Genes. J Pers Med 2023; 13:jpm13030550. [PMID: 36983731 PMCID: PMC10052610 DOI: 10.3390/jpm13030550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
Background: Rotundine is an herbal medicine with anti-cancer effects. However, little is known about the anti-cancer effect of rotundine on colorectal cancer. Therefore, our study aimed to investigate the specific molecular mechanism of rotundine inhibition of colorectal cancer. Methods: MTT and cell scratch assay were performed to investigate the effects of rotundine on the viability, migration, and invasion ability of SW480 cells. Changes in cell apoptosis were analyzed by flow cytometry. DEGs were detected by high-throughput sequencing after the action of rotundine on SW480 cells, and the DEGs were subjected to function enrichment analysis. Bioinformatics analyses were performed to screen out prognosis-related DEGs of COAD. Followed by enrichment analysis of prognosis-related DEGs. Furthermore, prognostic models were constructed, including ROC analysis, risk curve analysis, PCA and t-SNE, Nomo analysis, and Kaplan–Meier prognostic analysis. Results: In this study, we showed that rotundine concentrations of 50 μM, 100 μM, 150 μM, and 200 μM inhibited the proliferation, migration, and invasion of SW480 cells in a time- and concentration-dependent manner. Rotundine does not induce SW480 cell apoptosis. Compared to the control group, high-throughput results showed that there were 385 DEGs in the SW480 group. And DEGs were associated with the Hippo signaling pathway. In addition, 16 of the DEGs were significantly associated with poorer prognosis in COAD, with MEF2B, CCDC187, PSD2, RGS16, PLXDC1, HELB, ASIC3, PLCH2, IGF2BP3, CLHC1, DNHD1, SACS, H1-4, ANKRD36, and ZNF117 being highly expressed in COAD and ARV1 being lowly expressed. Prognosis-related DEGs were mainly enriched in cancer-related pathways and biological functions, such as inositol phosphate metabolism, enterobactin transmembrane transporter activity, and enterobactin transport. Prognostic modeling also showed that these 16 DEGs could be used as predictors of overall survival prognosis in COAD patients. Conclusions: Rotundine inhibits the development and progression of colorectal cancer by regulating the expression of these prognosis-related genes. Our findings could further provide new directions for the treatment of colorectal cancer.
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22
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Wei RY, Li CH, Zhong WY, Ye JJ. A correlation study affecting survival in patients after radical colon cancer surgery: A retrospective study. Medicine (Baltimore) 2023; 102:e33302. [PMID: 36930115 PMCID: PMC10019116 DOI: 10.1097/md.0000000000033302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/24/2023] [Indexed: 03/18/2023] Open
Abstract
The objective of this study was to explore the relevant factors affecting the 5-year survival rate of patients after radical colon cancer surgery, and to provide some basis for improving the quality of life and prognosis of colon cancer patients. The clinical data of 116 colon cancer patients who underwent treatment in our hospital from January 2017 to December 2017 were retrospectively selected. Using the date of performing surgical treatment as the starting point and the completion of 5 years after surgery or patient death as the end point, all patients were followed up by telephone to count the 5-year survival rate and analyze the influence of each factor with the prognosis of colon cancer patients. Of the 116 patients, 14 patients were lost to follow-up. Of the 102 patients with complete follow-up, 33 patients were died, with an overall 5-year survival rate of 67.6%. After univariate analysis, it was found that distant metastasis (χ2 = 10.493, P = .001), lymph node metastasis (χ2 = 25.145, P < .001), depth of muscle infiltration (χ2 = 14.929, P < .001), alcohol consumption (χ2 = 15.263, P < .001), and preoperative obstruction (χ2 = 9.555, P = .002) were significantly associated with the prognosis of colon cancer patients. Multivariate logistic analysis showed that distant metastasis (odds ratio [OR]: 1.932, 95% confidence intervals [CI]: 1.272-2.934, P = .002), lymph node metastasis (OR: 1.219, 95% CI: 1.091-1.362, P < .001), and obstruction (OR: 1.970, 95% CI: 1.300-2.990, P < .001) were significant independent risk factors affecting the prognosis in patients after radical colon cancer surgery. In summary, preoperative obstruction, lymph node metastasis, and distant metastasis are independent factors influencing 5-year survival rate after radical colon cancer surgery. Patients with risk factors should be followed up more closely and reasonable postoperative adjuvant chemotherapy regimens should be used to improve long-term survival.
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Affiliation(s)
- Ruo-Yu Wei
- Shenzhen School of Clinic Medicine, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Chun-Hong Li
- The First School of Clinic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wen-Yi Zhong
- The First School of Clinic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jin-Jun Ye
- Department of General Surgery, Longgang Central Hospital of Longgang District (The Ninth People’s Hospital of Shenzhen), Shenzhen, Guangdong, China
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23
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Huang E, Huang J. Music Therapy: A Noninvasive Treatment to Reduce Anxiety and Pain of Colorectal Cancer Patients—A Systemic Literature Review. Medicina (B Aires) 2023; 59:medicina59030482. [PMID: 36984483 PMCID: PMC10051791 DOI: 10.3390/medicina59030482] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/27/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Background and Objectives: Music interventions have been used for patients with cancer to meet their psychological, physical, social, and spiritual needs. This review identified the efficacy of music therapy among adult patients with colorectal cancer (CRC). Materials and Methods: We searched the PubMed/MEDLINE, CINAHL, and Cochrane Library databases. Only randomized controlled studies reported in English of patients with CRC were included. Two reviewers independently extracted data on patients and intervention measurements. The main outcomes included pain, anxiety, quality of life, mood, nausea, vomiting, vital signs. Results: A total of 147 articles were identified from the search. A total of 10 studies were included in the review. Nine out of the ten studies (90%) showed statistically and clinically significant improvements across the outcome variables. Only one study (10%) found no significant positive effect from music therapy in any of the measured outcomes. Among the seven studies measuring pain as an outcome, four studies (57%) demonstrated that music therapy reduced pain. Three studies (75%) showed that MT reduced anxiety. Conclusions: This systemic review indicates that music therapy might help reduce pain and anxiety for cancer patients, including those with colorectal cancer, who are receiving treatment in palliative care, inpatient care and outpatient care settings.
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Affiliation(s)
- Evan Huang
- Carrollwood Day School, Tampa, FL 33613, USA
| | - Jeffrey Huang
- Department of Anesthesiology, H. Lee Moffitt Cancer Center, Tampa, FL 33613, USA
- Department of Oncological Science, University of South Florida, Tampa, FL 33613, USA
- Correspondence: ; Tel.: +1-(813)-745-4673
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24
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Zhang Z, Shen C, Zhou F, Zhang Y. Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species-mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin-resistant colorectal cancer cells. Drug Dev Res 2023; 84:542-555. [PMID: 36779379 DOI: 10.1002/ddr.22044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/16/2023] [Accepted: 01/27/2023] [Indexed: 02/14/2023]
Abstract
Oxaliplatin (OXA) has been recognized as a third-generation platinum-based chemotherapeutic agent with stellar therapeutic efficacy in managing colorectal cancer (CRC). Nevertheless, resistance to OXA in CRC patients hinders its effectiveness. Shikonin (SHI), a natural naphthoquinone derived from Arnebia euchroma (Royle) Johnst., features a broad pharmacological profile and minimal toxicities. To assess the synergism of SHI and OXA towards OXA-resistant CRC cells (HCT116R ), we employed in vitro and in vivo pharmacological assays. Our experiments provided evidence that SHI, either alone or in combination with OXA, considerably reduced cell proliferation, triggered apoptosis, and induced the generation of reactive oxygen species (ROS) in HCT116R cells. Furthermore, the combination of SHI and OXA dramatically curbed the extent of HCT116R -initiated xenograft growth in mouse models. Bioinformatics, western blot, and ROS assays highlighted that the mechanisms of SHI against OXA-resistant CRC cells may involve the induction of cellular responses to chemical stress, intrinsic apoptosis, as well as endoplasmic reticulum stress pathways mediated by ROS. Notably, the synergism of SHI+OXA was partially abrogated by an ROS inhibitor N-acetyl cysteine. Our findings imply the potential of SHI to boost the sensitivity of OXA to CRC, offering promising benefits for clinical strategies to combat OXA resistance.
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Affiliation(s)
- Zhengguang Zhang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Cunsi Shen
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fuqiong Zhou
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Yajie Zhang
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
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25
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Zhu Y, Meng M, Hou Z, Wang W, Li L, Guan A, Wang R, Tang W, Yang F, Zhao Y, Gao H, Xie H, Li R, Tan J. Impact of cytotoxic T lymphocytes immunotherapy on prognosis of colorectal cancer patients. Front Oncol 2023; 13:1122669. [PMID: 36726382 PMCID: PMC9885253 DOI: 10.3389/fonc.2023.1122669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Background Expansion and activation of cytotoxic T lymphocytes (CTLs) in vitro represents a promising immunotherapeutic strategy, and CTLs can be primed by dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) transformed by recombinant adeno-associated virus (rAAV). This study aimed to explore the impact of rAAV-DC-induced CTLs on prognosis of CRC and to explore factors associated with prognosis. Methods This prospective observational study included patients operated for CRC at Yan'an Hospital Affiliated to Kunming Medical University between 2016 and 2019. The primary outcome was progression-free survival (PFS), secondary outcomes were overall survival (OS) and adverse events. Totally 49 cases were included, with 29 and 20 administered rAAV-DC-induced CTL and chemotherapy, respectively. Results After 37-69 months of follow-up (median, 54 months), OS (P=0.0596) and PFS (P=0.0788) were comparable between two groups. Mild fever occurred in 2 (6.9%) patients administered CTL infusion. All the chemotherapy group experienced mild-to-moderate adverse effects, including vasculitis (n=20, 100%), vomiting (n=5, 25%), nausea (n=17, 85%) and fatigue (n=17, 85%). Conclusions Lymphatic metastasis (hazard ratio [HR]=4.498, 95% confidence interval [CI]: 1.290-15.676; P=0.018) and lower HLA-I expression (HR=0.294, 95%CI: 0.089-0.965; P=0.044) were associated with poor OS in the CTL group. CTLs induced by rAAV-DCs might achieve comparable effectiveness in CRC patients compare to chemotherapy, cases with high tumor-associated HLA-I expression and no lymphatic metastasis were more likely to benefit from CTLs.
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Affiliation(s)
- Yankun Zhu
- Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Mingyao Meng
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Zongliu Hou
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Wenju Wang
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Lin Li
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Aoran Guan
- Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Ruotian Wang
- Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Weiwei Tang
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Fang Yang
- Department of Pathology, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Yiyi Zhao
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Hui Gao
- Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Hui Xie
- Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Ruhong Li
- Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China,*Correspondence: Ruhong Li, ; Jing Tan,
| | - Jing Tan
- Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, China,*Correspondence: Ruhong Li, ; Jing Tan,
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26
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Variation of Saponins in Sanguisorba officinalis L. before and after Processing ( Paozhi) and Its Effects on Colon Cancer Cells In Vitro. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27249046. [PMID: 36558181 PMCID: PMC9785891 DOI: 10.3390/molecules27249046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The incidence of colon cancer is increasing year over year, seriously affecting human health and quality of life in recent years. However, traditional Chinese medicine (TCM) has been utilized for the treatment of colon cancer. S. officinalis Saponins (S-Saponins), the potential compound of TCM, displays multiple biological activities in colon cancer treatment. In our study, ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with multivariate statistical analysis were performed to analyze and identify raw and processed saponins. Then, MTT and cell migration assays were used to preliminarily explore the effects of saponins in vitro on colon cancer cells. The results showed that 29 differential saponins compounds under Paozhi were identified by UHPLC-MS/MS. Moreover, in vitro validation showed that Sprocessed better inhibited the proliferation and migration of colon cancer cells than Sraw. This study provides a basis for the determination of the chemical fundamentals of the efficacy changes during Paozhi through inferring the changes in saponin components and its possible transformation mechanisms before and after processing S. officinalis. Meanwhile, it also provides new insights into potential bioactive ingredients for the treatment of colon cancer.
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27
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Zhang X, Huang H, Sun S, Li D, Sun L, Li Q, Chen R, Lai X, Zhang Z, Zheng X, Wong WL, Wen S. Induction of Apoptosis via Inactivating PI3K/AKT Pathway in Colorectal Cancer Cells Using Aged Chinese Hakka Stir-Fried Green Tea Extract. Molecules 2022; 27:molecules27238272. [PMID: 36500365 PMCID: PMC9737789 DOI: 10.3390/molecules27238272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Food extract supplements, with high functional activity and low side effects, play a recognized role in the adjunctive therapy of human colorectal cancer. The present study reported a new functional beverage, which is a type of Chinese Hakka stir-fried green tea (HSGT) aged for several years. The extracts of the lyophilized powder of five HSGT samples with different aging periods were analyzed with high-performance liquid chromatography. The major components of the extract were found to include polyphenols, catechins, amino acids, catechins, gallic acid and caffeine. The tea extracts were also investigated for their therapeutic activity against human colorectal cancer cells, HT-29, an epithelial cell isolated from the primary tumor. The effect of different aging time of the tea on the anticancer potency was compared. Our results showed that, at the cellular level, all the extracts of the aged teas significantly inhibited the proliferation of HT-29 in a concentration-dependent manner. In particular, two samples prepared in 2015 (15Y, aged for 6 years) and 2019 (19Y, aged for 2 years) exhibited the highest inhibition rate for 48 h treatment (cell viability was 50% at 0.2 mg/mL). Further, all the aged tea extracts examined were able to enhance the apoptosis of HT-29 cells (apoptosis rate > 25%) and block the transition of G1/S phase (cell-cycle distribution (CSD) from <20% to >30%) population to G2/M phase (CSD from nearly 30% to nearly 10%) at 0.2 mg/mL for 24 h or 48 h. Western blotting results also showed that the tea extracts inhibited cyclin-dependent kinases 2/4 (CDK2, CDK4) and CylinB1 protein expression, as well as increased poly ADP-ribose polymerase (PRAP) expression and Bcl2-associated X (Bax)/B-cell lymphoma-2 (Bcl2) ratio. In addition, an upstream signal of one of the above proteins, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling, was found to be involved in the regulation, as evidenced by the inhibition of phosphorylated PI3K and AKT by the extracts of the aged tea. Therefore, our study reveals that traditional Chinese aged tea (HSGT) may inhibit colon cancer cell proliferation, cell-cycle progression and promoted apoptosis of colon cancer cells by inactivating PI3K/AKT signalling.
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Affiliation(s)
- Xinyue Zhang
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Haiying Huang
- Tea Research Institute, Meizhou Academy of Agriculture and Forestry Sciences, Meizhou 514071, China
| | - Shili Sun
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Dongli Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
| | - Lingli Sun
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Qiuhua Li
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Ruohong Chen
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Xingfei Lai
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Zhenbiao Zhang
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Xi Zheng
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
| | - Wing-Leung Wong
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
- Correspondence: (W.-L.W.); (S.W.)
| | - Shuai Wen
- Tea Research Institute, Guangdong Key Laboratory of Tea Resources Innovation & Utilization/Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
- Correspondence: (W.-L.W.); (S.W.)
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Qian X, Zhao Y, Zhang T, Fan P. Downregulation of MACC1 facilitates the reversal effect of verapamil on the chemoresistance to active metabolite of irinotecan in human colon cancer cells. Heliyon 2022; 8:e11294. [PMID: 36345514 PMCID: PMC9636468 DOI: 10.1016/j.heliyon.2022.e11294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/13/2022] [Accepted: 10/24/2022] [Indexed: 11/09/2022] Open
Abstract
The aim of this study is to investigate the reversal effect of verapamil (VER) on chemoresistance to irinotecan (CPT-11) in human colon cancer cells and relevant mechanisms. Cell counting kit-8 (CCK-8) test and colony-forming unit (CFU) experiment results show that VER strengthens the sensitivity of human colon cancer cell line HT29 to CPT-11 but has a small effect on SW480 cells. High-throughput transcriptome sequencing, RT-PCR, and Western blot results show that the inhibition of metastasis-associated in colon cancer-1 (MACC1) expression by VER is the key factor for reversal effect on chemoresistance to CPT-11. Transfection experiments further show that VER can reverse the resistance of human colon cancer cells to SN-38, the active metabolite of CPT-11, when MACC1 is overexpressed. The nude mouse transplantation tumor experiment provides an in vivo proof that VER can strengthen sensitivity to CPT-11 in drug-resistant human colon cancer cells, and the effect might be related to the inhibited expression of MACC1. In summary, VER might strengthen the reversal effect of VER on chemoresistance to CPT-11 in human colon cancer cells and facilitate the apoptosis of human colon cancer cells by downregulating MACC1 expression.
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Affiliation(s)
- Xiaotao Qian
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China,The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China,Department of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, China
| | - Yongxin Zhao
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Tengyue Zhang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Pingsheng Fan
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China,The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China,Corresponding author.
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Zhang Z, Zhu Q, Wang S, Shi C. Epigallocatechin-3-gallate inhibits the formation of neutrophil extracellular traps and suppresses the migration and invasion of colon cancer cells by regulating STAT3/CXCL8 pathway. Mol Cell Biochem 2022; 478:887-898. [PMID: 36112238 DOI: 10.1007/s11010-022-04550-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/26/2022] [Indexed: 11/30/2022]
Abstract
Colon cancer is a common malignant tumor of the digestive tract. Tea catechin exerts anti-tumor effects in colon cancer. This work aimed to determine the functions of epigallocatechin-3-gallate (EGCG), one of the main active components of Tea catechins, in the progression of colon cancer. In this work, enzyme-linked immune-sorbent assay, quantitative real-time PCR and western blotting was utilized to examine the levels of IL-1β, TNF-α, STAT3, p-STAT3 and CXCL8 in colon cancer patients and healthy controls. Compared with healthy controls, the levels of IL-1β and TNF-α were significantly increased in the peripheral blood of colon cancer patients, and the expression of STAT3, p-STAT3 and CXCL8 was elevated in the neutrophils derived from colon cancer patients. Moreover, neutrophils were treated with phorbol ester (PMA) or DNase I to induce or impede the formation of neutrophil extracellular traps (NETs). Both STAT3 overexpression and PMA treatment promoted the expression of CXCL8, myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit) in the colon cancer-derived neutrophils, indicating that STAT3 overexpression facilitated the formation of NETs. STAT3 deficiency suppressed the formation of NETs, which consistent with the results of DNase I treatment. Transwell assay was utilized to detect the migration and invasion of colon cancer cell line SW480. EGCG treatment suppressed the formation of NETs and the expression of STAT3 and CXCL8 in the colon cancer-derived neutrophils, and then inhibited the migration and invasion of SW480 cells. In conclusion, this work demonstrated that EGCG inhibited the formation of NETs and subsequent suppressed the migration and invasion of colon cancer cells by regulating STAT3/CXCL8 signalling pathway. Thus, this study suggests that EGCG may become a potential drug for colon cancer therapy.
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Affiliation(s)
- Zhuoxian Zhang
- Department of Oncology, Gaoxin Branch Of The First Affiliated Hospital Of Nanchang University, No.7889, Changdong avenue, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Qiuli Zhu
- Department of Genetics, Gaoxin Branch Of The First Affiliated Hospital Of Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Siya Wang
- Department of Oncology, Gaoxin Branch Of The First Affiliated Hospital Of Nanchang University, No.7889, Changdong avenue, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Chao Shi
- Department of Oncology, Gaoxin Branch Of The First Affiliated Hospital Of Nanchang University, No.7889, Changdong avenue, Nanchang, 330006, Jiangxi Province, People's Republic of China.
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Banerjee A, Singh LP, Ikuse T. Editorial: Cancer of gastrointestinal tract: Novel insight into the molecular mechanisms related to inflammation and therapeutic targets. Front Pharmacol 2022; 13:970491. [PMID: 36110540 PMCID: PMC9468969 DOI: 10.3389/fphar.2022.970491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/01/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Aditi Banerjee
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
- *Correspondence: Aditi Banerjee,
| | | | - Tamaki Ikuse
- Department of Pediatric and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Polyphyllin I Promotes Autophagic Cell Death and Apoptosis of Colon Cancer Cells via the ROS-Inhibited AKT/mTOR Pathway. Int J Mol Sci 2022; 23:ijms23169368. [PMID: 36012632 PMCID: PMC9409257 DOI: 10.3390/ijms23169368] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/14/2022] [Accepted: 08/16/2022] [Indexed: 12/03/2022] Open
Abstract
Colon cancer is a common malignant tumor of the digestive tract, and it is considered among the biggest killers. Scientific and reasonable treatments can effectively improve the survival rate of patients if performed in the early stages. Polyphyllin I (PPI), a pennogenyl saponin isolated from Paris polyphylla var. yunnanensis, has exhibited strong anti-cancer activities in previous studies. Here, we report that PPI exhibits a cytotoxic effect on colon cancer cells. PPI suppressed cell viability and induced autophagic cell death in SW480 cells after 12 and 24 h, with the IC50 values 4.9 ± 0.1 μmol/L and 3.5 ± 0.2 μmol/L, respectively. Furthermore, we found PPI induced time-concentration-dependent autophagy and apoptosis in SW480 cells. In addition, down-regulated AKT/mTOR activity was found in PPI-treated SW480 cells. Increased levels of ROS might link to autophagy and apoptosis because reducing the level of ROS by antioxidant N-acetylcysteine (NAC) treatment mitigated PPI-induced autophagy and apoptosis. Although we did not know the molecular mechanism of how PPI induced ROS production, this is the first study to show that PPI induces ROS production and down-regulates the AKT/mTOR pathway, which subsequently promotes the autophagic cell death and apoptosis of colon cancer cells. This present study reports PPI as a potential therapeutic agent for colon cancer and reveals its underlying mechanisms of action.
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Tan L, Peng D, Cheng Y. Significant position of C-myc in colorectal cancer: a promising therapeutic target. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2295-2304. [PMID: 35972682 DOI: 10.1007/s12094-022-02910-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/23/2022] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is a malignant tumor initiating from the mucosa of the colorectum. According to the 2020 statistics from the World Health Organization, there are 10.0% CRC cases among all 19.3 million new cancers, followed by lung and breast cancer, and 9.4% CRC cases among all 9.9 million cancer deaths, ranking second. The population of CRC patients in China is large, and its incidence and mortality continue to increase each year. Despite the continuous development of surgical methods, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the overall survival of CRC patients remains low. Past research has suggested that c-myc plays a pivotal role in the development of CRC. A higher expression level of c-Myc is a negative prognostic marker in CRC. However, there are few drugs targeting c-myc directly. Therefore, we focused on discovering the mechanism of c-myc in CRC to provide a reference for a better therapy choice for patients.
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Affiliation(s)
- Li Tan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Yong Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Plant-Derived Bioactive Compounds in Colorectal Cancer: Insights from Combined Regimens with Conventional Chemotherapy to Overcome Drug-Resistance. Biomedicines 2022; 10:biomedicines10081948. [PMID: 36009495 PMCID: PMC9406120 DOI: 10.3390/biomedicines10081948] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/25/2022] [Accepted: 08/08/2022] [Indexed: 11/21/2022] Open
Abstract
Acquired drug resistance represents a major clinical problem and one of the biggest limitations of chemotherapeutic regimens in colorectal cancer. Combination regimens using standard chemotherapeutic agents, together with bioactive natural compounds derived from diet or plants, may be one of the most valuable strategies to overcome drug resistance and re-sensitize chemoresistant cells. In this review, we highlight the effect of combined regimens based on conventional chemotherapeutics in conjunction with well-tolerated plant-derived bioactive compounds, mainly curcumin, resveratrol, and EGCG, with emphasis on the molecular mechanisms associated with the acquired drug resistance.
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Liu H, Hu Y, Qi B, Yan C, Wang L, Zhang Y, Chen L. Network pharmacology and molecular docking to elucidate the mechanism of pulsatilla decoction in the treatment of colon cancer. Front Pharmacol 2022; 13:940508. [PMID: 36003525 PMCID: PMC9393233 DOI: 10.3389/fphar.2022.940508] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/28/2022] [Indexed: 01/01/2023] Open
Abstract
Objective: Colon cancer is a malignant neoplastic disease that seriously endangers the health of patients. Pulsatilla decoction (PD) has some therapeutic effects on colon cancer. This study is based on the analytical methods of network pharmacology and molecular docking to study the mechanism of PD in the treatment of colon cancer. Methods: Based on the Traditional Chinese Medicine Systems Pharmacology Database, the main targets and active ingredients in PD were filtered, and then, the colon cancer-related targets were screened using Genecards, OMIM, PharmGKB, and Drugbank databases. Then, the screened drug and disease targets were Venn analyzed to obtain the intersection targets. Cytoscape software was used to construct the “Components–Targets–Pathway” map, and the String database was used to analyze the protein interaction network of the intersecting targets and screen the core targets, and then, the core targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Molecular docking was implemented using AutoDockTools to predict the binding capacity for the core targets and the active components in PD. Results: Sixty-five ingredients containing 188 nonrepetitive targets were screened and 180 potential targets of PD anticolon cancer were identified, including 10 core targets, namely, MAPK1, JUN, AKT1, TP53, TNF, RELA, MAPK14, CXCL8, ESR1, and FOS. The results of GO analysis showed that PD anticolon cancer may be related to cell proliferation, apoptosis, energy metabolism, immune regulation, signal transduction, and other biological processes. The results of KEGG analysis indicated that the PI3K-Akt signaling pathway, MAPK signaling pathway, proteoglycans in cancer, IL-17 signaling pathway, cellular senescence, and TNF signaling pathway were mainly involved in the regulation of tumor cells. We further selected core targets with high degree values as receptor proteins for molecular docking with the main active ingredients of the drug, including MAPK1, JUN, and AKT1. The docking results showed good affinity, especially quercetin. Conclusion: This study preliminarily verified that PD may exert its effect on the treatment of colon cancer through multi-ingredients, multitargets, and multipathways. This will deepen our understanding of the potential mechanisms of PD anticolon cancer and establish a foundation for further basic experimental research.
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Affiliation(s)
- Huan Liu
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yuting Hu
- College of Integration Science, Yanbian University, Yanji, China
- *Correspondence: Yuting Hu, ; Liang Chen,
| | - Baoyu Qi
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Chengqiu Yan
- Anorectal Diagnosis and Treatment Center, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Lin Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yiwen Zhang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Liang Chen
- Anorectal Diagnosis and Treatment Center, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Yuting Hu, ; Liang Chen,
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Cao W, Zhang B, Liu Y. Expression of Long Nonencoding Ribonucleic Acid SNHG20 in Colon Cancer Tissue in Its Influences on Chemotherapeutic Sensitivity of Colon Cancer Cells. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4752782. [PMID: 35915794 PMCID: PMC9338858 DOI: 10.1155/2022/4752782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/17/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022]
Abstract
Noncoding RNA (ncRNA) is a kind of RNA that plays a key role in a variety of biological processes, illnesses, and tumours despite the fact that it cannot be translated into proteins. The HT29 colon cancer cell line was utilized to create a 5-FU drug-resistant cell strain (control group), a lentivirus SNHG20 carrier (OE-SNHG20 group), and an SNHG20 shRNA carrier (SNHG20 shRNA carrier group) (SE-SNHG20 group). To determine the expression of cell SNHG20, a real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was utilized, and cholecystokinin-octapeptide (CCK-8) was used to detect the difference in 5-FU inhibitory concentration 50. The goal of the study was to see how variations in long nonencoding ribonucleic acid (lncRNA) SNHG20 expression affect colon cancer cell 5-fluorouracil (5-FU) chemotherapeutic sensitivity by collecting colon cancer and normal para cancer tissues and analysing the differences in SNHG20 expression. The ability of cell cladogenesis was tested using platform cladogenesis. Cell apoptosis was detected using flow cytometry. Western blots revealed the presence of protein phosphatidylinositol kinase (PI3K), protein kinase B (AKT), caspase-3, e-cadherin, and matrix metalloproteinase 9 (MMP-9) enzymes. The findings revealed that SNHG20 expression was considerably upregulated (P < 0.05) in colon cancer tissue and 5-FU drug-resistant colon cancer cells. Cell 5-FU IC50, cell cladogenesis, cell survival rate, and MMP-9, P-PI3K, and P-AKT expression were all significantly improved. Cell apoptosis and expressions of E-cadherin and caspase-3, on the other hand, were considerably decreased (P < 0.05). Cell 5-FU IC50, cell cladogenesis, cell survival rate, and the expressions of MMP-9, P-PI3K, and P-AKT were all significantly lower in the SE-SNHG20 group, although cell apoptosis and the expressions of E-cadherin and caspase-3 were significantly higher (P < 0.05). The results revealed that lncRNA SNHG20 could inhibit the chemotherapeutic sensitivity of colon cancer cells to 5-FU by regulating PI3K/AKT pathways. The inhibition of lncRNA SNHG20 expression could promote the apoptosis and proliferation of 5-FU-resistant colon cancer cells.
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Affiliation(s)
- Wenbin Cao
- North China University of Science and Technology Affiliated Hospital, Tangshan, 063000 Hebei, China
| | - Bo Zhang
- North China University of Science and Technology Affiliated Hospital, Tangshan, 063000 Hebei, China
| | - Yang Liu
- North China University of Science and Technology Affiliated Hospital, Tangshan, 063000 Hebei, China
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Novoa Díaz MB, Carriere P, Gigola G, Zwenger AO, Calvo N, Gentili C. Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide. World J Gastroenterol 2022; 28:3177-3200. [PMID: 36051345 PMCID: PMC9331538 DOI: 10.3748/wjg.v28.i26.3177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/21/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Parathyroid hormone-related peptide (PTHrP) plays a key role in the development and progression of many tumors. We found that in colorectal cancer (CRC) HCT116 cells, the binding of PTHrP to its receptor PTHR type 1 (PTHR1) activates events associated with an aggressive phenotype. In HCT116 cell xenografts, PTHrP modulates the expression of molecular markers linked to tumor progression. Empirical evidence suggests that the Met receptor is involved in the development and evolution of CRC. Based on these data, we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC cells.
AIM To elucidate the relationship among PTHR1, PTHrP, and Met in CRC models.
METHODS For in vitro assays, HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP (1-34) (10-8 M). Where indicated, cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide, the vehicle of the inhibitors. The protein levels were evaluated by Western blot technique. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the changes in gene expression. Wound healing assay and morphological monitoring were performed to evaluate cell migration and changes related to the epithelial-mesenchymal transition (EMT), respectively. The number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan (CPT-11), oxaliplatin (OXA), or doxorubicin (DOXO) with or without PTHrP. For in vivo tests, HCT116 cell xenografts on 6-wk-old male N:NIH (S)_nu mice received daily intratumoral injections of PTHrP (40 μg/kg) in 100 μL phosphate-buffered saline (PBS) or the vehicle (PBS) as a control during 20 d. Humanitarian slaughter was carried out and the tumors were removed, weighed, and fixed in a 4% formaldehyde solution for subsequent treatment by immunoassays. To evaluate the expression of molecular markers in human tumor samples, we studied 23 specimens obtained from CRC patients which were treated at the Hospital Interzonal de Graves y Agudos Dr. José Penna (Bahía Blanca, Buenos Aires, Argentina) and the Hospital Provincial de Neuquén (Neuquén, Neuquén, Argentina) from January 1990 to December 2007. Seven cases with normal colorectal tissues were assigned to the control group. Tumor tissue samples and clinical histories of patients were analyzed. Paraffin-embedded blocks from primary tumors were reviewed by hematoxylin-eosin staining technique; subsequently, representative histological samples were selected from each patient. From each paraffin block, tumor sections were stained for immunohistochemical detection. The statistical significance of differences was analyzed using proper statistical analysis. The results were considered statistically significant at P < 0.05.
RESULTS By Western blot analysis and using total Met antibody, we found that PTHrP regulated Met expression in HCT116 cells but not in Caco-2 cells. In HCT116 cells, Met protein levels increased at 30 min (P < 0.01) and at 20 h (P < 0.01) whereas the levels diminished at 3 min (P < 0.05), 10 min (P < 0.01), and 1 h to 5 h (P < 0.01) of PTHrP treatment. Using an active Met antibody, we found that where the protein levels of total Met decreased (3 min, 10 min, and 60 min of PTHrP exposure), the status of phosphorylated/activated Met increased (P < 0.01) at the same time, suggesting that Met undergoes proteasomal degradation after its phosphorylation/activation by PTHrP. The increment of its protein level after these decreases (at 30 min and 20 h) suggests a modulation of Met expression by PTHrP in order to improve Met levels and this idea is supported by our observation that the cytokine increased Met mRNA levels at least at 15 min in HCT116 cells as revealed by RT-qPCR analysis (P < 0.05). We then proceeded to evaluate the signaling pathways that mediate the phosphorylation/ activation of Met induced by PTHrP in HCT116 cells. By Western blot technique, we observed that PP1, a specific inhibitor of the activation of the proto-oncogene protein tyrosine kinase Src, blocked the effect of PTHrP on Met phosphorylation (P < 0.05). Furthermore, the selective inhibition of the ERK 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) using PD98059 and the p38 MAPK using SB203580 diminished the effect of PTHrP on Met phosphorylation/activation (P < 0.05). Using SU11274, the specific inhibitor of Met activation, and trypan blue dye exclusion test, Western blot, wound healing assay, and morphological analysis with a microscope, we observed the reversal of cell events induced by PTHrP such as cell proliferation (P < 0.05), migration (P < 0.05), and the EMT program (P < 0.01) in HCT116 cells. Also, PTHrP favored the chemoresistance to CPT-11 (P < 0.001), OXA (P < 0.01), and DOXO (P < 0.01) through the Met pathway. Taken together, these findings suggest that Met activated by PTHrP participates in events associated with the aggressive phenotype of CRC cells. By immunohistochemical analysis, we found that PTHrP in HCT116 cell xenografts enhanced the protein expression of Met (0.190 ± 0.014) compared to tumors from control mice (0.110 ± 0.012; P < 0.05) and of its own receptor (2.27 ± 0.20) compared to tumors from control mice (1.98 ± 0.14; P < 0.01). Finally, assuming that the changes in the expression of PTHrP and its receptor are directly correlated, we investigated the expression of both Met and PTHR1 in biopsies of CRC patients by immunohistochemical analysis. Comparing histologically differentiated tumors with respect to those less differentiated, we found that the labeling intensity for Met and PTHR1 increased and diminished in a gradual manner, respectively (P < 0.05).
CONCLUSION PTHrP acts through the Met pathway in CRC cells and regulates Met expression in a CRC animal model. More basic and clinical studies are needed to further evaluate the PTHrP/Met relationship.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Graciela Gigola
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | | | - Natalia Calvo
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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Wu L, Li S, Shu P, Liu Q. Effect of miR-488 on Colon Cancer Biology and Clinical Applications. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:2138954. [PMID: 35571741 PMCID: PMC9098289 DOI: 10.1155/2022/2138954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 11/22/2022]
Abstract
Objective To explore the expression levels of miR-488, miR-29c-3p, and growth differentiation factor 15 (GDF15) in colon cancer tissue and analyze their relationship with clinicopathological features in patients with colon cancer. Methods The study was conducted from November 2012 to November 2020. A total of 200 patients with colon cancer were treated in our hospital during this period. During the operation, the colon cancer tissues and the adjacent tissues whose distance from the cancer tissues were more than 5 cm were collected, and the expression levels of miR-488, miR-29c-3p, and GDF15 mRNA in colon cancer tissues were detected by qRT-PCR (real-time fluorescence quantitative). The relationship between them and the clinicopathological features and prognosis of patients with colon cancer were analyzed and discussed. Results The level of miR-488 in colon cancer tissues was lower than that in adjacent tissues, but the levels of miR-29c-3p and GDF15 mRNA in colon cancer tissues were higher than those in adjacent tissues (P < 0.05). Compared with paracancerous tissues, the expression rates of miR-29c-3p and GDF15 protein were higher in colon cancer tissues (P < 0.05). There was no difference in age, sex, tumor location, and tumor diameter between high expression of miR-488 group and low expression of miR-488 group (P > 0.05). The degree of differentiation, depth of invasion, TNM stage, lymph node metastasis, and other factors have a direct impact on the level of miR-488 and the expression of miR-29c-3p (P < 0.05). The depth of invasion, TNM stage, and lymph node metastasis could affect the expression of GDF15 in patients with colon cancer (P < 0.05). Conclusion miR-488, miR-29c-3p, and GDF15 in colon cancer tissue are related to the clinicopathological features of patients in varying degrees and may become markers after early warning of colon cancer, which can provide effective guidance for clinical diagnosis and treatment.
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Affiliation(s)
- Liangqin Wu
- Department of Gastroenterology, Anhui No.2 Provincial People's Hospital, Hefei, Anhui, China
| | - Songguo Li
- Department of Pathology, Anhui No.2 Provincial People's Hospital, Hefei, Anhui, China
| | - Peng Shu
- Department of Gastroenterology, Anhui No.2 Provincial People's Hospital, Hefei, Anhui, China
| | - Qian Liu
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing, Jiangsu, China
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38
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Ryu TY, Kim K, Han TS, Lee MO, Lee J, Choi J, Jung KB, Jeong EJ, An DM, Jung CR, Lim JH, Jung J, Park K, Lee MS, Kim MY, Oh SJ, Hur K, Hamamoto R, Park DS, Kim DS, Son MY, Cho HS. Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer. THE ISME JOURNAL 2022; 16:1205-1221. [PMID: 34972816 PMCID: PMC9038766 DOI: 10.1038/s41396-021-01119-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 09/08/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022]
Abstract
The human microbiome plays an essential role in the human immune system, food digestion, and protection from harmful bacteria by colonizing the human intestine. Recently, although the human microbiome affects colorectal cancer (CRC) treatment, the mode of action between the microbiome and CRC remains unclear. This study showed that propionate suppressed CRC growth by promoting the proteasomal degradation of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) through HECT domain E3 ubiquitin protein ligase 2 (HECTD2) upregulation. In addition, EHMT2 downregulation reduced the H3K9me2 level on the promoter region of tumor necrosis factor α-induced protein 1 (TNFAIP1) as a novel direct target of EHMT2. Subsequently, TNFAIP1 upregulation induced the apoptosis of CRC cells. Furthermore, using Bacteroides thetaiotaomicron culture medium, we confirmed EHMT2 downregulation via upregulation of HECTD2 and TNFAIP1 upregulation. Finally, we observed the synergistic effect of propionate and an EHMT2 inhibitor (BIX01294) in 3D spheroid culture models. Thus, we suggest the anticancer effects of propionate and EHMT2 as therapeutic targets for colon cancer treatment and may provide the possibility for the synergistic effects of an EHMT2 inhibitor and microbiome in CRC treatment.
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Affiliation(s)
- Tae Young Ryu
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.,Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Kwangho Kim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Tae-Su Han
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Mi-Ok Lee
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Jinkwon Lee
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Jinhyeon Choi
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Kwang Bo Jung
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Eun-Jeong Jeong
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Da Mi An
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Cho-Rok Jung
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Jung Hwa Lim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jaeeun Jung
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Kunhyang Park
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Moo-Seung Lee
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Mi-Young Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Soo Jin Oh
- Asan Institute for Life Sciences, Asan Medical Center and Department of Convergence Medicine, College of Medicine, University of Ulsan, Seoul, 05505, Republic of Korea
| | - Keun Hur
- Department of Biochemistry and Cell biology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Ryuji Hamamoto
- Division of Molecular Modification and Cancer Biology, National Cancer Center, Tokyo, 104-0045, Japan
| | - Doo-Sang Park
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea. .,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
| | - Dae-Soo Kim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea. .,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
| | - Mi-Young Son
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea. .,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
| | - Hyun-Soo Cho
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea. .,Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
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39
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Dark-Lumen Magnetic Resonance Image Based on Artificial Intelligence Algorithm in Differential Diagnosis of Colon Cancer. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:4217573. [PMID: 35387249 PMCID: PMC8977291 DOI: 10.1155/2022/4217573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022]
Abstract
This research was aimed o investigate the application value and diagnostic effect of dark-lumen magnetic resonance imaging (dark-lumen MRI) based on artificial intelligence algorithm on colon cancer. A total of 98 patients with ulcerated colon cancer were selected as the study subjects. All patients underwent colonic endoscopy. The patients were divided into algorithm group (artificial intelligence algorithm processing image group) and control group (conventional method processing image group) according to different dark-lumen MRI processing methods. The detection efficiency of colon cancer was compared between the two groups. It showed that the diagnostic effect of dark-lumen MRI based on artificial intelligence algorithm was significant. The apparent diffusion coefficient (ADC) in the control group was 0.92 ± 0.14 mm2/s (minimum: 0.74, maximum: 1.30), ADC in the algorithm group was 1.55 ± 0.31 mm2/s (minimum: 1.22, maximum: 2.42). The ADC of patients in algorithm group was significantly higher than that of patients in control group, with statistical difference (t = 7.827, P < 0.001). The correct number of cases was 46 and the diagnostic error number was 3 in algorithm group, with accuracy of 93%. The correct number of cases was 41 and the diagnostic error number was 8 in control group, with accuracy of 83%. In comparison, the correct rate was 10% higher in algorithm group, indicating that the diagnostic effect was better in algorithm group. The mean value of invasion depth was 10.42 in the algorithm group and 5.27 in the control group, indicating that the algorithm group was more accurate in the judgment of invasion depth, had a good prospect of clinical application, and had guiding significance for the diagnosis of colon cancer.
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40
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Morimoto Y, Takahashi H, Arita A, Itakura H, Fujii M, Sekido Y, Hata T, Fujino S, Ogino T, Miyoshi N, Uemura M, Matsuda C, Yamamoto H, Mizushima T, Doki Y, Eguchi H. High postoperative carcinoembryonic antigen as an indicator of high‑risk stage II colon cancer. Oncol Lett 2022; 23:167. [PMID: 35414828 PMCID: PMC8988258 DOI: 10.3892/ol.2022.13287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/17/2022] [Indexed: 11/30/2022] Open
Abstract
Postoperative carcinoembryonic antigen (post-CEA) has recently been reported to be a reliable prognostic factor for colon cancer. However, most clinicians decide whether or not to conduct adjuvant chemotherapy (AC) for stage II colon cancer according to major guidelines, which do not include post-CEA in their high-risk criteria. The present study aimed to assess post-CEA in stage II colon cancer for which the significance of AC is unknown. The present study analyzed 199 consecutive patients with stage II colon cancer who underwent curative surgery between January 2007 and December 2016. The CEA value was considered high when it was ≥5.0 ng/ml. The prognostic value of high post-CEA values was assessed. Overall, 19 patients exhibited high post-CEA levels. Kaplan-Meier survival curve analysis demonstrated that patients with high post-CEA levels had significantly worse relapse-free survival (RFS) and overall survival (OS) than those with normal post-CEA [RFS, 63.5 (high post-CEA) vs. 88.0% (normal post-CEA), P=0.003; OS, 76.5 (high post-CEA) vs. 96.8% (normal post-CEA), P<0.001]. Multivariate analysis demonstrated that high post-CEA remained a significant independent risk factor for worse RFS [hazard ratio (HR), 3.98; P=0.006]. The same was also demonstrated for patients without AC (HR, 5.43; P=0.008). To the best of our knowledge, the present study was the first to demonstrate that high post-CEA levels may be an indicator of high-risk stage II colon cancer, even for patients without AC. These results highlight the need for a multicenter prospective study.
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Affiliation(s)
- Yoshihiro Morimoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Asami Arita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Hiroaki Itakura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Makoto Fujii
- Department of Mathematical Health Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Yuki Sekido
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Tsuyoshi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Shiki Fujino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
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Farinha P, Pinho JO, Matias M, Gaspar MM. Nanomedicines in the treatment of colon cancer: a focus on metallodrugs. Drug Deliv Transl Res 2022; 12:49-66. [PMID: 33616870 DOI: 10.1007/s13346-021-00916-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 02/06/2023]
Abstract
Worldwide, colon cancer (CC) represents the fourth most common type of cancer and the fifth major cause of cancer-associated deaths. Surgical resection is considered the standard therapeutic choice for CC in early stages. However, in latter stages of the disease, adjuvant chemotherapy is essential for an appropriate management of this pathology. Metal-based complexes displaying cytotoxic properties towards tumor cells emerge as potential chemotherapeutic options. One metallodrug, oxaliplatin, was already approved for clinical use, playing an important role in the treatment of CC patients. Unfortunately, most of the newly designed metal-based complexes exhibit lack of selectivity against cancer cells, low solubility and permeability, high dose-limiting toxicity, and emergence of resistances. Nanodelivery systems enable the incorporation of metallodrugs at adequate payloads, solving the above-referred drawbacks. Moreover, drug delivery systems, depending on their physicochemical properties, are able to release the incorporated material preferentially at affected tissues/organs, enhancing the therapeutic activity in vivo, with concomitant fewer side effects. In this review, the general features and therapeutic management of CC will be addressed, with a special focus on preclinical or clinical studies using metal-based compounds. Furthermore, the use of different nanodelivery systems will also be described as tools to potentiate the therapeutic index of metallodrugs for the management of CC.
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Affiliation(s)
- Pedro Farinha
- Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
| | - Jacinta O Pinho
- Faculty of Pharmacy, Research Institute for Medicines, iMed.ULisboa, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
| | - Mariana Matias
- Faculty of Pharmacy, Research Institute for Medicines, iMed.ULisboa, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
| | - M Manuela Gaspar
- Faculty of Pharmacy, Research Institute for Medicines, iMed.ULisboa, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
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42
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Yue B, Gao R, Lv C, Yu Z, Wang H, Geng X, Wang Z, Dou W. Berberine Improves Irinotecan-Induced Intestinal Mucositis Without Impairing the Anti-colorectal Cancer Efficacy of Irinotecan by Inhibiting Bacterial β-glucuronidase. Front Pharmacol 2021; 12:774560. [PMID: 34795594 PMCID: PMC8593678 DOI: 10.3389/fphar.2021.774560] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/04/2021] [Indexed: 12/21/2022] Open
Abstract
Irinotecan (CPT11), a broad-spectrum cytotoxic anticancer agent, induces a series of toxic side-effects. The most conspicuous side-effect is gastrointestinal mucositis, including nausea, vomiting, and diarrhea. A growing body of evidence indicates that bacteria β-glucuronidase (GUS), an enzyme expressed by intestinal microbiota, converts the inactive CPT11 metabolite SN38G to the active metabolite SN38 to ultimately induce intestinal mucositis. We sought to explore the potential efficacy and underlying mechanisms of berberine on CPT11-induced mucositis. Our study showed that berberine (50 mg/kg; i. g.) mitigated the CPT11-induced loss of mucosal architecture, ulceration, and neutrophil infiltration. Meanwhile, berberine improved mucosal barrier function by increasing the number of globlet cells, protecting trans-endothelial electrical resistance (TEER), reducing permeability and increasing tight junction proteins expression. LC-MS analysis showed that berberine decreased the content of SN38 in feces, which correlated with decreases in both GUS activity and GUS-producing bacteria. Further molecular docking and Lineweaver-Burk plots analyses suggested that berberine functions as a potential non-competitive inhibitor against GUS enzyme. Of note, berberine maintained the anti-tumor efficacy of CPT11 in a tumor xenograft model while abrogating the intestinal toxicity of CPT11. Overall, we identified for the first time the remission effects of berberine on intestinal mucositis induced by CPT11 without impairing the anti-colorectal cancer efficacy of CPT11 partially via inhibiting bacterial GUS enzyme.
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Affiliation(s)
- Bei Yue
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Ruiyang Gao
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Cheng Lv
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Zhilun Yu
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Hao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Xiaolong Geng
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Wei Dou
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
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43
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Surgical Oncology: Multidisciplinarity to Improve Cancer Treatment and Outcomes. Curr Oncol 2021; 28:4471-4473. [PMID: 34898580 PMCID: PMC8628680 DOI: 10.3390/curroncol28060379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 11/17/2022] Open
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44
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Yue B, Gao R, Wang Z, Dou W. Microbiota-Host-Irinotecan Axis: A New Insight Toward Irinotecan Chemotherapy. Front Cell Infect Microbiol 2021; 11:710945. [PMID: 34722328 PMCID: PMC8553258 DOI: 10.3389/fcimb.2021.710945] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 09/23/2021] [Indexed: 12/19/2022] Open
Abstract
Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly dividing cells (e.g., cancer cells, epithelial cells, hematopoietic cells) and commensal bacteria. Therefore, CPT11 can induce a series of toxic side-effects, of which the most conspicuous is gastrointestinal toxicity (nausea, vomiting, diarrhea). Studies have shown that the gut microbiota modulates the host response to chemotherapeutic drugs. Targeting the gut microbiota influences the efficacy and toxicity of CPT11 chemotherapy through three key mechanisms: microbial ecocline, catalysis of microbial enzymes, and immunoregulation. This review summarizes and explores how the gut microbiota participates in CPT11 metabolism and mediates host immune dynamics to affect the toxicity and efficacy of CPT11 chemotherapy, thus introducing a new concept that is called "microbiota-host-irinotecan axis". Also, we emphasize the utilization of bacterial β-glucuronidase-specific inhibitor, dietary interventions, probiotics and strain-engineered interventions as emergent microbiota-targeting strategies for the purpose of improving CPT11 chemotherapy efficiency and alleviating toxicity.
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Affiliation(s)
- Bei Yue
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Ruiyang Gao
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Wei Dou
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
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45
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Geng Q, Wei Q, Shen Z, Zheng Y, Wang L, Xue W, Li L, Zhao J. Comprehensive Analysis of the Prognostic Value and Immune Infiltrates of the Three-m5C Signature in Colon Carcinoma. Cancer Manag Res 2021; 13:7989-8002. [PMID: 34707405 PMCID: PMC8542737 DOI: 10.2147/cmar.s331549] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/10/2021] [Indexed: 12/28/2022] Open
Abstract
Background The 5-methylcytosine (m5C) is one of the important forms of RNA post modification, and its regulatory mechanism in tumors has received increasing attention. However, its potential role in colorectal cancer remains unclear. Materials and Methods Here, we systematically investigated the genetic variation and prognostic value of the 14 m5c RNA methylation regulators in colon cancer. The prognostic risk score was constructed using three m5C regulators, which was verified in the GSE17536 (N=177), GSE41258 (N=248) and GSE38832 (N=122) datasets. Results The risk score developed from the three-m5C signature represents an independent prognostic factor, which can accurately predict the prognosis of patients with colon cancer in multiple datasets. The cytokine–cytokine receptor interaction and chemokine signaling pathway were significantly enriched in the low-risk score group. Further analysis showed that the three-m5C signature was related to tumor immune microenvironment (TIME), affecting the abundance of tumor-infiltrating immune cells. Especially, patients with low risk score had higher immune score than those with high risk score. In addition, gene set enrichment analysis (GSEA) confirmed that all three regulatory factors are associated with the MAPK/p38 signaling pathway. Conclusion In conclusion, our study illustrates that the three-m5C signature may be involved in the regulation of colon cancer immune microenvironment in synergy with the MAPK signaling pathway. Therefore, further studying the three-m5C signature regulatory mechanisms might provide promising targets for improving the responsiveness of colon cancer to immunotherapy.
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Affiliation(s)
- Qishun Geng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.,Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Qian Wei
- Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Zhibo Shen
- Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yuanyuan Zheng
- Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Longhao Wang
- Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Wenhua Xue
- Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Lifeng Li
- Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.,Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
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Jiao Y, Liu Q, Zhao H, Hu X, Sun J, Liu X. Changes and Prognostic Value of lncRNA CASC9 in Patients with Advanced Colon Cancer after Chemotherapy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:1858974. [PMID: 34589129 PMCID: PMC8476242 DOI: 10.1155/2021/1858974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/29/2021] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Colon cancer (CC) shows a gradual increasing incidence in recent years, and chemotherapy is a frequently adopted treatment for patients with middle or advanced colon cancer (ACC), but it lacks prognostic markers after CC. METHODS The changes of lncRNA CASC9 in 58 patients with CC were determined using a real-time quantitative PCR (qRT-PCR) assay before and after chemotherapy, and the correlation of serum lncRNA CASC9 with efficacy of FOLFOX4 regimen (oxaliplatin + calcium folinate + fluorouracil) was analyzed. The patients were followed up to understand the association of lncRNA CASC9 with overall survival (OS) and progression-free survival (PFS). RESULTS Patients with CC showed notably higher lncRNA CASC9 expression than controls, and lncRNA CASC9 presented an association with the clinical stage of the patients. In addition, lncRNA CASC9 demonstrated a clinical value in predicting efficacy on patients and acted as one independent prognostic factor for PFS in patients with ACC. CONCLUSIONS With increased expression of serum lncRNA CASC9, patients with ACC suffered an unfavorable chemotherapy effect. In addition, serum lncRNA CASC9 is a promising sensitive indicator for prediction of ACC and is related to the clinical efficacy and prognosis of patients.
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Affiliation(s)
- Yingwei Jiao
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Qiang Liu
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Hongbo Zhao
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Xianzhen Hu
- Four Departments of General Surgery, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Jinlong Sun
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Xiaohong Liu
- Department of Traditional Chinese Medicine, Baoji Maternal and Child Health Care Hospital, Baoji, Shaanxi 721000, China
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Li H, Hou YX, Yang Y, He QQ, Gao TH, Zhao XF, Huo ZB, Chen SB, Liu DX. Tetramethylpyrazine inhibits proliferation of colon cancer cells in vitro. World J Clin Cases 2021; 9:4542-4552. [PMID: 34222421 PMCID: PMC8223836 DOI: 10.12998/wjcc.v9.i18.4542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/27/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colon cancer is one of the most common malignancies worldwide, and chemotherapy is a widely used strategy in colon cancer clinical therapy. However, chemotherapy resistance is a major cause of disease recurrence and progression in colon cancer, and thus novel drugs for treatment are urgently needed. Tetramethylpyrazine (TMP), a component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in tumors.
AIM To investigate the potential anticancer activity of TMP in colon cancer and its underlying mechanisms.
METHODS Colon cancer cells were incubated with different concentrations of TMP. Cell viability was evaluated by crystal violet staining assay and cell counting kit-8 assay, and cell apoptosis and cell cycle were assessed by flow cytometry.
RESULTS TMP significantly inhibited the proliferation of colon cancer cells in a dose- and time-dependent manner. In addition, flow cytometry revealed that TMP induced cell cycle arrest at the G0/G1 phase. TMP treatment caused early stage apoptosis in SW480 cells, whereas it caused late stage apoptosis in HCT116 cells.
CONCLUSION Our studies demonstrated that TMP inhibits the proliferation of colon cancer cells in a dose- and time-dependent manner by inducing apoptosis and arresting the cell cycle at the G0/G1 phase. Our findings suggest that TMP might serve as a potential novel therapeutic drug in the treatment of human colon cancer.
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Affiliation(s)
- Hua Li
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Yan-Xu Hou
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Yu Yang
- School of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Qing-Qiang He
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Tian-Hua Gao
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Xiao-Feng Zhao
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Zhi-Bin Huo
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Shu-Bo Chen
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Deng-Xiang Liu
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
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48
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Spinelli S, Mini E, Monteleone E, Angiolini C, Roviello G. ALTERTASTE: improving food pleasure and intake of oncology patients receiving chemotherapy. Future Oncol 2021; 17:2573-2579. [PMID: 33858202 DOI: 10.2217/fon-2020-0871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
ALTERTASTE is a prospective study to evaluate changes in taste/flavor perception and food preferences in patients treated with adjuvant or neoadjuvant chemotherapy for breast or colorectal cancer. The study adopts a longitudinal approach. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and their psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors. Furthermore, the trial aims to develop an easy and reliable procedure to test smell, taste and food behavior alterations to allow a routine measure with patients. Clinical trial registration: NCT04495387 (ClinicalTrials.gov).
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Affiliation(s)
- Sara Spinelli
- Department of Agriculture, Food, Environment & Forestry - Section of Food Science & Technology, University of Florence, Via Donizetti 6, Florence, 50144, Italy
| | - Enrico Mini
- Department of Health Sciences, Section of Clinical Pharmacology & Oncology, University of Florence, Viale Pieraccini, 6, Florence, 50139, Italy
| | - Erminio Monteleone
- Department of Agriculture, Food, Environment & Forestry - Section of Food Science & Technology, University of Florence, Via Donizetti 6, Florence, 50144, Italy
| | - Catia Angiolini
- Breast Oncology, Careggi University Hospital, Viale Pieraccini, 6, Florence, 50139, Florence, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology & Oncology, University of Florence, Viale Pieraccini, 6, Florence, 50139, Italy
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De Oliveira T, Goldhardt T, Edelmann M, Rogge T, Rauch K, Kyuchukov ND, Menck K, Bleckmann A, Kalucka J, Khan S, Gaedcke J, Haubrock M, Beissbarth T, Bohnenberger H, Planque M, Fendt SM, Ackermann L, Ghadimi M, Conradi LC. Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo. Cancers (Basel) 2021; 13:1011. [PMID: 33671096 PMCID: PMC7957803 DOI: 10.3390/cancers13051011] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 02/14/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients' long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. MATERIALS AND METHODS The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. RESULTS High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. CONCLUSION The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.
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Affiliation(s)
- Tiago De Oliveira
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
| | - Tina Goldhardt
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
| | - Marcus Edelmann
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
| | - Torben Rogge
- Institute of Organic and Biomolecular Chemistry, Tammannstraβe 2, 37077 Göttingen, Germany; (T.R.); (K.R.); (L.A.)
| | - Karsten Rauch
- Institute of Organic and Biomolecular Chemistry, Tammannstraβe 2, 37077 Göttingen, Germany; (T.R.); (K.R.); (L.A.)
| | - Nikola Dobrinov Kyuchukov
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
| | - Kerstin Menck
- Clinic of Hematology and Medical Oncology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany; (K.M.); (A.B.)
- Department of Medicine Medical Clinic A, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Annalen Bleckmann
- Clinic of Hematology and Medical Oncology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany; (K.M.); (A.B.)
- Department of Medicine Medical Clinic A, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Joanna Kalucka
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, DK-Aarhus C, 8000 Aarhus, Denmark;
- Aarhus Institute of Advanced Studies (AIAS), Aarhus University, 8000 Aarhus, Denmark
| | - Shawez Khan
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark;
| | - Jochen Gaedcke
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
| | - Martin Haubrock
- Institute of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077 Göttingen, Germany; (M.H.); (T.B.)
| | - Tim Beissbarth
- Institute of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077 Göttingen, Germany; (M.H.); (T.B.)
| | - Hanibal Bohnenberger
- Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany;
| | - Mélanie Planque
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; (M.P.); (S.-M.F.)
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; (M.P.); (S.-M.F.)
| | - Lutz Ackermann
- Institute of Organic and Biomolecular Chemistry, Tammannstraβe 2, 37077 Göttingen, Germany; (T.R.); (K.R.); (L.A.)
| | - Michael Ghadimi
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
| | - Lena-Christin Conradi
- Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (T.D.O.); (T.G.); (M.E.); (N.D.K.); (J.G.); (M.G.)
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50
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Wu ZX, Yang Y, Zeng L, Patel H, Bo L, Lin L, Chen ZS. Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line. Front Oncol 2021; 10:624954. [PMID: 33692943 PMCID: PMC7937870 DOI: 10.3389/fonc.2020.624954] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 12/21/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo.
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Affiliation(s)
- Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States
| | - Yuqi Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States
| | - Leli Zeng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.,Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Harsh Patel
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States
| | - Letao Bo
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States
| | - Lusheng Lin
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States
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