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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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Liu W, Wang Y, Xia L, Li J. Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer. Nutrients 2024; 16:797. [PMID: 38542707 PMCID: PMC10975298 DOI: 10.3390/nu16060797] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 01/04/2025] Open
Abstract
As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.
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Affiliation(s)
| | | | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
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Zhao C, Qiu L, Wu D, Zhang M, Xia W, Lv H, Cheng L. Targeted reversal of multidrug resistance in ovarian cancer cells using exosome‑encapsulated tetramethylpyrazine. Mol Med Rep 2024; 29:25. [PMID: 38099342 PMCID: PMC10784732 DOI: 10.3892/mmr.2023.13148] [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: 07/20/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
The objective of the present study was to develop exosomes (EXOs) encapsulating tetramethylpyrazine (TMP) for the reversal of drug resistance in ovarian cancer therapy. Human A2780 cells were incubated with TMP for 48 h. Purified TMP‑primed EXOs (EXOs‑TMP) were isolated through ultracentrifugation. The developed EXOs‑TMP were characterized using techniques such as transmission electron microscopy, nanoparticle tracking analysis, Fluorescence microscopy and western blotting. Subsequently, MTT, western blotting and flow cytometry assays were performed to evaluate the biological effects in drug‑resistant A2780T cells. The results demonstrated that the incorporation of TMP into EXOs exhibited an anti‑ovarian cancer effect and markedly enhanced the antitumor efficacy of paclitaxel (PTX). Furthermore, it was identified that the ability of EXO‑TMP to reverse cell resistance was associated with the downregulation of multidrug resistance protein 1, multidrug resistant‑associated protein 1 and glutathione S‑transferase Pi protein expression. Flow cytometry analysis revealed that EXO‑TMP induced apoptosis in drug‑resistant cells and enhanced the apoptotic effect when combined with PTX. EXOs are naturally sourced, exhibit excellent biocompatibility and enable precise drug delivery to target sites, thereby reducing toxic side effects. Overall, EXO‑TMP exhibited direct targeting capabilities towards A2780T cells and effectively reduced their drug resistance. EXOs‑TMP provide a novel and effective drug delivery pathway for reversing drug resistance in ovarian cancer.
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Affiliation(s)
- Chenge Zhao
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
- Department of Pharmacy, The Fifth Affiliated Hospital of Jinan University, Heyuan, Guangdong 517000, P.R. China
| | - Lulu Qiu
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Di Wu
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Ming Zhang
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Wanying Xia
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Huiyi Lv
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
- Dalian Kexiang Technology Development Co. Ltd, Dalian, Liaoning 116044, P.R. China
| | - Lichun Cheng
- Department of Pharmacy, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
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Feng Y, Wang K, Wang N, Jia P, Zhang L, Yuan H, Lu P, Lu Y, Zhang H, Li R, Zhang Y, Li Q, Zhang P. Tetramethylpyrazine protects neural stem cells against sevoflurane-induced toxicity through Akt/GSK-3β pathway. Metab Brain Dis 2022; 37:2457-2466. [PMID: 35838869 DOI: 10.1007/s11011-022-01008-2] [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: 01/12/2022] [Accepted: 05/16/2022] [Indexed: 11/28/2022]
Abstract
Sevoflurane, a commonly used anesthetic, has been found to cause neural stem cell (NSC) injury, thereby contributing to neurocognitive impairment following general anesthesia. Tetramethylpyrazine (TMP), one of the most widely used medicinal compounds isolated from a traditional Chinese herb, possess neuroprotective activity. However, its effect on sevoflurane-induced NSC injury remains unclear. NSCs were pretreated with indicated concentrations of TMP for 2 h and then exposed to sevoflurane for 6 h. Cell injury was measured using lactate dehydrogenase (LDH) release assay. Cell viability and proliferation were detected by cell counting kit-8 (CCK-8) assay and 5-bromo-2'-deoxyuridine (BrdU) labeling, respectively. Apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The levels of cleaved caspase-3, phosphorylated protein kinase B (Akt) and phosphorylated glycogen synthase kinase-3β (GSK-3β) were detected by western blotting. Our results showed exposure to sevoflurane decreased the viability and proliferation of NSCs, while TMP preserved NSC viability and proliferation after sevoflurane exposure. In addition, the expression of cleaved caspase-3 and TUNEL positive cells were markedly decreased in TMP-treated NSCs compared with the control. Furthermore, pretreatment with TMP significantly increased the levels of phosphorylated Akt and GSK-3β in sevoflurane-injured NSCs. However, an upstream inhibitor of Akt, LY294002 abolished the protective of TMP on the cell viability of NSCs. In conclusion, these findings indicate that TMP protects NSCs from sevoflurane-induced toxicity through Akt/GSK-3β pathway.
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Affiliation(s)
- Yan Feng
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
- Department of Anesthesiology, Xi'an People's Hospital (Xi'an Fourth Hospital), 710004, Xi'an, Shaanxi, China
| | - Kui Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Ning Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Pengyu Jia
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Lei Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
- Department of Anesthesiology, Xi'an People's Hospital (Xi'an Fourth Hospital), 710004, Xi'an, Shaanxi, China
| | - Haozheng Yuan
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Pan Lu
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Yang Lu
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Hong Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Rong Li
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Yan Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Qianqian Li
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China
| | - Pengbo Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157# West 5 Road, 710004, Xi'an, Shaanxi, China.
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Jung YY, Mohan CD, Eng H, Narula AS, Namjoshi OA, Blough BE, Rangappa KS, Sethi G, Kumar AP, Ahn KS. 2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells. Biomolecules 2022; 12:891. [PMID: 35883447 PMCID: PMC9312507 DOI: 10.3390/biom12070891] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 02/01/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.
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Affiliation(s)
- Young Yun Jung
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
| | | | - Huiyan Eng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | | | - Ojas A. Namjoshi
- Engine Biosciences, 733 Industrial Rd., San Carlos, CA 94070, USA;
| | - Bruce E. Blough
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27616, USA;
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
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Yang C, Mai Z, Liu C, Yin S, Cai Y, Xia C. Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113513. [PMID: 35684449 PMCID: PMC9181879 DOI: 10.3390/molecules27113513] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/13/2022]
Abstract
Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.
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Affiliation(s)
- Chuansheng Yang
- Department of Head-Neck and Breast Surgery, Yuebei People’s Hospital of Shantou University, Shaoguan 512027, China;
| | - Zhikai Mai
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Can Liu
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shuanghong Yin
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yantao Cai
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- Correspondence: (Y.C.); (C.X.)
| | - Chenglai Xia
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- Correspondence: (Y.C.); (C.X.)
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Ren J, Cai J, Wang C. Tetramethylpyrazine inhibits the proliferation, invasiveness and migration of cervical cancer C33A cells by retarding the Hedgehog signaling pathway. Oncol Lett 2022; 23:66. [PMID: 35069875 PMCID: PMC8756559 DOI: 10.3892/ol.2022.13185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/08/2021] [Indexed: 11/05/2022] Open
Affiliation(s)
- Jing Ren
- Department of Biochemistry, Shijiazhuang Medical College, Shijiazhuang, Hebei 050000, P.R. China
| | - Jiping Cai
- Department of Biochemistry, Shijiazhuang Medical College, Shijiazhuang, Hebei 050000, P.R. China
| | - Changfeng Wang
- Department of Biochemistry, Shijiazhuang Medical College, Shijiazhuang, Hebei 050000, P.R. China
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Yang S, Wu S, Dai W, Pang L, Xie Y, Ren T, Zhang X, Bi S, Zheng Y, Wang J, Sun Y, Zheng Z, Kong J. Tetramethylpyrazine: A Review of Its Antitumor Potential and Mechanisms. Front Pharmacol 2021; 12:764331. [PMID: 34975475 PMCID: PMC8716857 DOI: 10.3389/fphar.2021.764331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/18/2021] [Indexed: 11/13/2022] Open
Abstract
Cancer remains a major public health threat. The mitigation of the associated morbidity and mortality remains a major research focus. From a molecular biological perspective, cancer is defined as uncontrolled cell division and abnormal cell growth caused by various gene mutations. Therefore, there remains an urgent need to develop safe and effective antitumor drugs. The antitumor effect of plant extracts, which are characterized by relatively low toxicity and adverse effect, has attracted significant attention. For example, increasing attention has been paid to the antitumor effects of tetramethylpyrazine (TMP), the active component of the Chinese medicine Chuanqiong, which can affect tumor cell proliferation, apoptosis, invasion, metastasis, and angiogenesis, as well as reverse chemotherapeutic resistance in neoplasms, thereby triggering antitumor effects. Moreover, TMP can be used in combination with chemotherapeutic agents to enhance their effects and reduce the side effect associated with chemotherapy. Herein, we review the antitumor effects of TMP to provide a theoretical basis and foundation for the further exploration of its underlying antitumor mechanisms and promoting its clinical application.
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Affiliation(s)
- Shaojie Yang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuodong Wu
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wanlin Dai
- Innovation Institute of China Medical University, Shenyang, China
| | - Liwei Pang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yaofeng Xie
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tengqi Ren
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaolin Zhang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shiyuan Bi
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuting Zheng
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jingnan Wang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang Sun
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhuyuan Zheng
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing Kong
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Jing Kong,
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Wen A, Zhu Y, Mazhar M, Qin L, Zeng H, Zhu Y. Enhancement of Anti-Proliferative Activity of the Extracts from Dehulled Adlay by Fermentation with Bacillus subtilis. Foods 2021; 10:foods10122959. [PMID: 34945511 PMCID: PMC8701002 DOI: 10.3390/foods10122959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 01/18/2023] Open
Abstract
Dehulled adlay was fermented with Bacillus subtilis BJ3-2, the anti-proliferative activities of the extracts from fermented dehulled adlay were investigated with six types of tumor cells, and then the bioactive components and the anti-proliferative mechanism were primarily explored. Results showed that all the extracts of B.subtilis-fermented dehulled adlay (BDA) and dehulled adlay (DA) had no inhibition effect on human embryonic kidney 239T cells. The anti-proliferative activities of the extracts from BDA against six types of tumor cells were almost always significantly higher than DA. Compared with others, the n-butanol extract of BDA (BDA-Nb) exhibited stronger anti-proliferative activities against human leukemia K562 cells and human non-small cell lung cancer A549 cells. Importantly, the anti-proliferative activity of fermented dehulled adlay against K562 cells was firstly discovered. Meanwhile, BDA-Nb was rich in tetramethylpyrazine, γ-aminobutyric acid, protocatechuic, 2,3,4-trihydroxybenzoic, chlorogenic, p-hydroxybenzoic, caffeic, trans-cinnamic, ferulic acids, and rutin. BDA-Nb induced the proliferative inhibition of K562 and A549 cells due to abnormal cell morphology, the increased cell population in G1 phase and apoptosis rate, the downregulation of Bcl-2, and the upregulation of Bax and caspase-3/8/9. These results indicate that dehulled adlay fermented with B.subtilis could be a potential therapeutic agent for leukemia and lung cancer.
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Affiliation(s)
- Anyan Wen
- School of Liquor and Food Engineering, Guizhou University, Guiyang 550025, China; (A.W.); (Y.Z.); (H.Z.)
| | - Yong Zhu
- School of Liquor and Food Engineering, Guizhou University, Guiyang 550025, China; (A.W.); (Y.Z.); (H.Z.)
| | - Muhammad Mazhar
- College of Life Sciences, Guizhou University, Guiyang 550025, China;
| | - Likang Qin
- School of Liquor and Food Engineering, Guizhou University, Guiyang 550025, China; (A.W.); (Y.Z.); (H.Z.)
- Key Laboratory of Agricultural and Animal Products Storage and Processing of Guizhou Province, Guiyang 550025, China
- National & Local Joint Engineering Center for the Development and Utilization Technology of Drug and Food Resources in Southwest China, Guiyang 550025, China
- Correspondence:
| | - Haiying Zeng
- School of Liquor and Food Engineering, Guizhou University, Guiyang 550025, China; (A.W.); (Y.Z.); (H.Z.)
- Key Laboratory of Agricultural and Animal Products Storage and Processing of Guizhou Province, Guiyang 550025, China
| | - Yi Zhu
- Plant Protection and Plant Quarantine Station of Guizhou Province, Guiyang 550001, China;
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Zeng G, An H, Fang D, Wang W, Han Y, Lian C. Plantamajoside protects H9c2 cells against hypoxia/reoxygenation-induced injury through regulating the akt/Nrf2/HO-1 and NF-κB signaling pathways. J Recept Signal Transduct Res 2020; 42:125-132. [PMID: 33349091 DOI: 10.1080/10799893.2020.1859534] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Myocardial ischemia/reperfusion (I/R) injury has been found to be associated with oxidative stress. Plantamajoside (PMS) is a major compound of Plantago asiatica that was reported to possess cardioprotective and antioxidant effects. The current study was designed to investigate the effect of PMS on myocardial I/R injury. Rat cardiomyocytes H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to establish in vitro model of myocardial I/R injury. MTT assay proved that H9c2 cells viability was significant reduced under H/R treatment, while the reduction was ameliorated by PMS. H/R-induced ROS production in H9c2 cells was suppressed by PMS. The decreased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the H/R group were effectively elevated by PMS. In addition, treatment with PMS attenuated H/R-stimulated production of TNF-α, IL-6 and IL-1β in H9c2 cells. Besides, PMS significantly suppressed bax expression and caspase 3 activity, as well as increased bcl-2 expression in H/R-stimulated H9c2 cells. Furthermore, we also found that PMS significantly enhanced the activation of Akt/Nrf2/HO-1 signaling pathway and suppressed the activation of NF-κB signaling pathway in H/R-stimulated H9c2 cells. These results provided substantial evidence that PMS protected against myocardial I/R injury via attenuating oxidative stress, inflammatory response and apoptosis. The protective effects of PMS were attributed to the Akt/Nrf2/HO-1 and NF-κB signaling pathways.
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Affiliation(s)
- Guangwei Zeng
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Huixian An
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Dong Fang
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Wei Wang
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Yang Han
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Cheng Lian
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
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11
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Role of Curcumin and (-)-Epigallocatechin-3- O-Gallate in Bladder Cancer Treatment: A Review. Cancers (Basel) 2020; 12:cancers12071801. [PMID: 32635637 PMCID: PMC7408736 DOI: 10.3390/cancers12071801] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/26/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
The incidence of bladder cancer (BC) is increasing, and although current therapeutic approaches are effective in many cases, recurrence of BC is common. Therefore, it seems necessary to search not only for novel therapeutic approaches, but also for new therapeutic agents. Natural polyphenols, such as curcumin (CUR) and epigallocatechin gallate (EGCG), possess remarkable antitumor activity. Their biochemical mechanisms of action include regulation of signaling pathways, modeling of proteins involved in apoptosis and cell cycle inhibition, angiogenesis, and the proliferation, migration and adhesion of tumor cells. Both compounds also present antioxidant, anti-inflammatory, antibacterial and antiviral properties. CUR has been considered a promising candidate for the treatment of cystic fibrosis, Alzheimer's disease or malaria, whereas EGCG can play a supportive role in the treatment of obesity, metabolic and neurodegenerative diseases. The review summarizes the latest research on the role of CUR and EGCG in the treatment of BC. In particular, the effects of CUR and EGCG, and their prospects for use in BC therapy, their inhibition of cancer development and their prevention of multidrug resistance, are described. The literature's data indicate the possibility of achieving the effect of synergism of both polyphenols in BC therapy, which has been observed so far in the treatment of ovarian, breast and prostate cancer.
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12
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Tinoush B, Shirdel I, Wink M. Phytochemicals: Potential Lead Molecules for MDR Reversal. Front Pharmacol 2020; 11:832. [PMID: 32636741 PMCID: PMC7317022 DOI: 10.3389/fphar.2020.00832] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/20/2020] [Indexed: 12/14/2022] Open
Abstract
Multidrug resistance (MDR) is one of the main impediments in the treatment of cancers. MDR cancer cells are resistant to multiple anticancer drugs. One of the major mechanisms of MDR is the efflux of anticancer drugs by ABC transporters. Increased activity and overexpression of these transporters are important causes of drug efflux and, therefore, resistance to cancer chemotherapy. Overcoming MDR is a fundamental prerequisite for developing an efficient treatment of cancer. To date, various types of ABC transporter inhibitors have been employed but no effective anticancer drug is available at present, which can completely overcome MDR. Phytochemicals can reverse MDR in cancer cells via affecting the expression or activity of ABC transporters, and also through exerting synergistic interactions with anticancer drugs by addressing additional molecular targets. We have listed numerous phytochemicals which can affect the expression and activity of ABC transporters in MDR cancer cell lines. Phytochemicals in the groups of flavonoids, alkaloids, terpenes, carotenoids, stilbenoids, lignans, polyketides, and curcuminoids have been examined for MDR-reversing activity. The use of MDR-reversing phytochemicals with low toxicity to human in combination with effective anticancer agents may result in successful treatment of chemotherapy-resistant cancer. In this review, we summarize and discuss published evidence for natural products with MDR modulation abilities.
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Affiliation(s)
- Boshra Tinoush
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
| | - Iman Shirdel
- Marine Sciences Faculty, Tarbiat Modares University, Noor, Iran
| | - Michael Wink
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
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13
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Zhou Y, Zhou Z, Ji Z, Yan W, Li H, Yu X. Tetramethylpyrazine reduces prostate cancer malignancy through inactivation of the DPP10‑AS1/CBP/FOXM1 signaling pathway. Int J Oncol 2020; 57:314-324. [PMID: 32319592 DOI: 10.3892/ijo.2020.5036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 02/06/2020] [Indexed: 11/05/2022] Open
Abstract
Tetramethylpyrazine (TMP), a Chinese herbal medicine, has been reported to possess anticancer effects. Emerging evidence suggests that various long noncoding RNAs (lncRNAs) serve important roles in cancer initiation and progression. In the present study, the tumor‑suppressive effects of TMP in human PCa cells was examined and the underlying mechanisms of its actions were determined. The data showed that TMP treatment reduced cell viability and increased apoptosis in a dose‑dependent manner. Reverse transcription‑quantitative PCR showed TMP treatment increased the expression of lncRNA DPP10‑AS1 in PCa cells. Furthermore, DPP10‑AS1 was also upregulated in TMP‑resistant PCa cells. Knockdown of DPP10‑AS1 reversed TMP resistance, whereas increased expression of DPP10‑AS1 abrogated the TMP‑mediated cytotoxicity in PCa cells. In addition, forkhead box M1 (FOXM1) was verified as the functional target of DPP10‑AS1, and knockdown of FOXM1 reversed the TMP/DPP10‑AS1‑induced cell cytotoxicity. Mechanistically, DPP10‑AS1 was associated with CREB binding protein, thereby induced H3K27ac enrichment at the promoter region of the FOXM1 gene. In conclusion, the present study showed that TMP may be a promising treatment agent for PCa and lncRNA DPP10‑AS1 may be a promising therapeutic target for TMP treatment.
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Affiliation(s)
- Yi Zhou
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Zhien Zhou
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Zhigang Ji
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Weigang Yan
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Hanzhong Li
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Xiao Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
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Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3 γ/Bcl-2. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5820415. [PMID: 31885804 PMCID: PMC6914960 DOI: 10.1155/2019/5820415] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 08/28/2019] [Accepted: 09/11/2019] [Indexed: 02/08/2023]
Abstract
Doxorubicin (Dox) with cardiotoxicity and endotheliotoxicity limits its clinical application for cancer. The toxicitic mechanism involves excess ROS generation. 14-3-3s have the protective effects on various injured tissues and cells. Tetramethylpyrazine (TMP) is an alkaloid extracted from the rhizome of Ligusticum wallichii and has multiple bioactivities. We hypothesize that TMP has the protective effects on vascular endothelium by upregulating 14-3-3γ. To test the hypothesis, Dox-induced endotheliotoxicity was used to establish vascular endothelium injury models in mice and human umbilical vein endothelial cells. The effects of TMP were assessed by determining thoracic aortic strips' endothelium-dependent dilation (EDD), as well as LDH, CK, caspase-3, SOD, CAT, GSH-Px activities and MDA level in serum, apoptotic rate, and histopathological changes of vascular tissue (in vivo). Also, cell viability, LDH and caspase-3 activities, ROS generation, levels of NAD+/NADH and GSH/GSSG, MMP, mPTP opening, and apoptotic rate were evaluated (in vitro). The expression of 14-3-3γ and Bcl-2, as well as phosphorylation of Bad (S112), were determined by Western blot. Our results showed that Dox-induced injury to vascular endothelium was decreased by TMP via upregulating 14-3-3γ expression in total protein and Bcl-2 expression in mitochondria, activating Bad (S112) phosphorylation, maintaining EDD, reducing LDH, CK, and caspase-3 activities, thereby causing a reduction in apoptotic rate, and histopathological changes of vascular endothelium (in vivo). Furthermore, TMP increased cell viability and MMP levels, maintained NAD+/NADH, GSH/GSSG balance, decreased LDH and caspase-3 activities, ROS generation, mPTP opening, and apoptotic rate (in vitro). However, the protective effects to vascular endothelium of TMP were significantly canceled by pAD/14-3-3γ-shRNA, an adenovirus that caused knockdown 14-3-3γ expression, or ABT-737, a specific Bcl-2 inhibitor. In conclusion, this study is the first to demonstrate that TMP protects the vascular endothelium against Dox-induced injury via upregulating 14-3-3γ expression, promoting translocation of Bcl-2 to the mitochondria, closing mPTP, maintaining MMP, inhibiting RIRR mechanism, suppressing oxidative stress, improving mitochondrial function, and alleviating Dox-induced endotheliotoxicity.
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15
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Li Y, Zu X, Hu X, Wang L, He W. Forkhead Box R2 Knockdown Decreases Chemoresistance to Cisplatin via MYC Pathway in Bladder Cancer. Med Sci Monit 2019; 25:8928-8939. [PMID: 31761897 PMCID: PMC6894368 DOI: 10.12659/msm.917345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Bladder cancer is a very common urological cancer globally, and cisplatin- or gemcitabine-based chemotherapy is essential for advanced bladder cancer patients. Many patients with bladder cancer have a relatively poor response to chemotherapy, leading to failure of clinical treatment. We mined the GSE77883 GEO dataset, identifying FoxR2 as being a significantly upregulated gene in T24 chemoresistant cells. Herein, we assessed how FoxR2 functions in bladder cancer cell chemoresistance. Material/Methods Cisplatin-resistant T24 (T24/DDP) cells were constructed by administering increasing concentrations of cisplatin, and differences in expression of FoxR2 were examined in T24/DDP and T24 cells. FoxR2 loss- and gain-of-function cells models were established in T24/DDP and T24 cells, respectively. Cell survival, clone formation, cell cycle, and cell apoptosis were assessed, and the MYC pathway was verified. Results FoxR2 was significantly upregulated in T24/DDP cells compared to T24 cells. Knockdown of FoxR2 in T24/DDP cells, survival rate, and clone formation were decreased, G1/S phase transition was suppressed, and cell apoptosis was promoted. These results were reversed by restoration of FoxR2 levels in T24 cells. We found that FoxR2 knockdown enhanced sensitivity to cisplatin, whereas MYC overexpression antagonized chemosensitivity in T24/DDP cells. Conclusions FoxR2 knockdown decreases chemoresistance to cisplatin via the MYC pathway in bladder cancer cells, and this may be a target for overcoming chemoresistance in bladder cancer.
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Affiliation(s)
- Yangle Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Xiongbing Zu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Xiheng Hu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Long Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Wei He
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
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16
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Ma W, Ma J, Lei T, Zhao M, Zhang M. Targeting immunotherapy for bladder cancer by using anti-CD3 × CD155 bispecific antibody. J Cancer 2019; 10:5153-5161. [PMID: 31602268 PMCID: PMC6775611 DOI: 10.7150/jca.29937] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 07/01/2019] [Indexed: 12/13/2022] Open
Abstract
To investigate whether CD155 is an attractive target for T cell-mediated immunotherapy against human bladder cancer, we examined the novel bispecific antibody anti-CD3 x anti-CD155 (CD155Bi-Ab) for its ability to redirect activated T cells (ATCs) to target bladder cancer cells was examined. Expression of CD155 was detected by flow cytometry on the surface of bladder cancer cells, including T24 and Pumc-91 cells, and their chemotherapeutic drug-resistant counterparts. ATCs generated from healthy donors were stimulated with anti-CD3 monoclonal antibody, anti-CD28 monoclonal antibody and interleukin-2 (IL-2) for 14 days. The cytotoxic activity of ATCs armed with CD155Bi-Ab against bladder cancer cells was detected by LDH and luciferase quantitative assay. Furthermore, ATCs generated from bladder cancer patients were also armed with CD155Bi-Ab to verity the cell killing by the same methods. In contrast to unarmed ATCs, CD155Bi-armed ATCs against bladder cancer cells were increased cytotoxic activity at effector/target (E/T) ratios of 5:1, 10:1, and 20:1, with more IFN-γ, TNF-α secreting. It is worth noting that in spite of the presence of immunosuppression in bladder cancer patients and the drug resistance in chemotherapeutic drug-resistant cancer cell lines, not only the anti-tumor effect of CD155Bi-armed ATCs generated from bladder cancer patients still showed significantly but only higher level of activation marker CD69 was expressed. Taken together, our results suggest that CD155 is an effective target for the CD155-positive bladder cancer. And CD155Bi-Ab-armed ATCs are promisingly to provide a novel strategy for current CD155-positive bladder cancer therapy.
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Affiliation(s)
- Wanru Ma
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China.,Collage of Medical Technique, Xuzhou Medical University, Jiangsu, China
| | - Juan Ma
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Ting Lei
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhao
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhang
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
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17
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Jiang X, Lei T, Zhang M. Expression and Functions of Formyl Peptide Receptor 1 in Drug-Resistant Bladder Cancer. Technol Cancer Res Treat 2019; 17:1533034618769413. [PMID: 29665744 PMCID: PMC5912276 DOI: 10.1177/1533034618769413] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Objective: To explore the correlation of formyl peptide receptor 1 expression with drug resistance and the functions of formyl peptide receptor 1 in drug-resistant bladder cancer. Methods: Expression of formyl peptide receptor 1 in T24 and T24/DDP cisplatin-resistant bladder cancer cell lines was tested by quantitative real-time Polymerase Chain Reaction and Western blotting. After incubation of T24/DDP with N-formyl-Met-Leu-Phe, the phosphor proteins were tested by Western blot analysis. We characterized the functions of formyl peptide receptor 1 in T24/DDP cells by assessing proliferation, migration, and changes of cell cycles. Results: Formyl peptide receptor 1 was expressed in both T24 and T24/DDP, and it was overexpressed in T24/DDP compared with T24. Formyl peptide receptor 1 activation promoted the expression of the messenger RNA of resistance-related proteins, such as multidrug resistance-associated protein 1 (MRP1) and lung resistance-related protein (LRP). The expression of 4 signal pathway proteins were upregulated: signal transducer and activator of transcription 3, Janus kinase 2, extracellular regulated protein kinases, and protein kinase B, while the expression of phosphatidylinositol 3-kinase was observed to be downregulated in drug-resistant bladder cancer cells. Formyl peptide receptor 1 activation also improved the expression of phospho-signal transducer and activator of transcription 3 and phospho-extracellular regulated protein kinases 1/2 and promoted the proliferation and migration of T24/DDP cells. In addition, formyl peptide receptor 1 inhibition led to the change in the cell cycle in T24/DDP. Conclusions: The overexpression of formyl peptide receptor 1 may be related to drug-resistant bladder cancer and promotes the deterioration of drug-resistant bladder cancer.
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Affiliation(s)
- Xue Jiang
- 1 Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,2 Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Ting Lei
- 1 Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,2 Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhang
- 1 Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,2 Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
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18
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Wu J, Li W, Ning J, Yu W, Rao T, Cheng F. Long noncoding RNA UCA1 targets miR-582-5p and contributes to the progression and drug resistance of bladder cancer cells through ATG7-mediated autophagy inhibition. Onco Targets Ther 2019; 12:495-508. [PMID: 30666128 PMCID: PMC6331189 DOI: 10.2147/ott.s183940] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Rently, the incidence of bladder cancer has been on the rise. Accumulating researches have been conducted to clarify the molecular mechanisms and potential therapeutic targets of bladder cancer. The present study aims to explore the regulatory mechanism of the urothelial carcinoma-associated 1 (UCA1)-miR-582-5p-ATG7 axis in bladder cancer. METHODS Quantitative real-time polymerase chain reaction was used to detect mRNA level. Relative protein expression was detected by western blot. wound healing assay and transwell were used to determine migration and invasion of cells. in addtion, luciferase reporter assay and immunohistochemistry were performed. RESULTS UCA1 expression was upregulated in bladder cancer tissues and cells, while the depletion of UCA1 by shRNA resulted in the suppression of cell proliferation, invasion, migration, and drug resistance. Further studies demonstrated that UCA1 could directly interact with miR-582-5p, and that there was an inverse correlation between miR-582-5p and UCA1. In addition, we found that ATG7 is a target of miR-582-5p and can be downregulated by either miR-582-5p overexpression or UCA1 knockdown. In particular, the autophagy is reduced when UCA1 shRNA is introduced. Moreover, the in vivo experiment further demonstrated the contribution of UCA1 in bladder cancer including tumor growth, invasion, and migration, and UCA1 knockdown can inhibit the aforementioned activities. CONCLUSION These results provided evidence for a novel UCA1 interaction regulatory network in bladder cancer, that is, UCA1-miR-582-5p-ATG7-autophagy axis. Our study provides a new insight into the treatment of bladder cancer.
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Affiliation(s)
- Junfeng Wu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Wei Li
- Department of Anesthesiology, People's Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Weimin Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
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Ma W, Ma J, Ma P, Lei T, Zhao M, Zhang M. Targeting immunotherapy for bladder cancer using anti-CD3× B7-H3 bispecific antibody. Cancer Med 2018; 7:5167-5177. [PMID: 30253078 PMCID: PMC6198238 DOI: 10.1002/cam4.1775] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 08/17/2018] [Accepted: 08/20/2018] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE B7-H3 is attractive for cancer immunotherapy with B7-H3 overexpressed tumors. To explore whether B7-H3 is an effective target for patients with bladder cancer, anti-CD3× anti-B7-H3 bispecific antibodies (B7-H3Bi-Ab) was armed with activated T cells (ATC) to kill bladder cancer cells. METHODS High expressions of B7-H3 on human bladder cancer cells were detected, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. ATC generated from healthy donors were stimulated with anti-CD3 monoclonal antibody and interleukin-2 (IL-2) for 13 days. The ability of ATC armed with B7-H3Bi-Ab to kill bladder cancer cells was detected by flow cytometry, LDH, Elisa, and luciferase quantitative assay. Moreover, ATC generated from bladder cancer patients was armed with B7-H3Bi-Ab to verity the cell killing by the methods as previously described. RESULTS Compared with unarmed ATC, a significant increased cytotoxicity of B7-H3Bi-Ab-armed ATC against bladder cancer cells was discovered. The B7-H3Bi-Ab-armed ATC secreted more IFN-γ, TNF-α, and expressed high levels of activation marker CD69. Interestingly, despite the presence of immunosuppression in patients and resistance in chemotherapeutic drug-resistant cancer cell lines, B7-H3Bi-Ab-armed ATC from patients with bladder cancer still showed significant cytotoxic activity against bladder cancer cells and their chemotherapeutic drug-resistant counterparts. CONCLUSION B7-H3 is an effective target for bladder cancer. B7-H3Bi-Ab enhances the ability of ATC to kill bladder cancer cells. B7-H3Bi-Ab-armed ATC is promisingly to provide a novel strategy for current bladder cancer therapy.
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Affiliation(s)
- Wanru Ma
- Collage of Medical Technique, Xuzhou Medical University, Jiangsu, China.,Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Juan Ma
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Ping Ma
- Collage of Medical Technique, Xuzhou Medical University, Jiangsu, China
| | - Ting Lei
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhao
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhang
- Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Peking University Ninth School of Clinical Medical, Beijing, China.,Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
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20
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Zhao HD, Xie HJ, Li J, Ren CP, Chen YX. Research Progress on Reversing Multidrug Resistance in Tumors by Using Chinese Medicine. Chin J Integr Med 2018; 24:474-480. [PMID: 29860581 DOI: 10.1007/s11655-018-2910-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Indexed: 10/14/2022]
Abstract
Multidrug resistance (MDR) is a major cause of cancer chemotherapy failure, and it is important to develop suitable reversal agents to overcome MDR. A majority of chemical reversal agents have acceptable reversal effects. However, the toxicity and adverse reactions associated with these agents restricts their clinical use. Chinese medicines (CMs) have lower toxicities and adverse reactions and are associated with multiple components, multiple targets and reduced toxicity. CMs have several advantages and could reverse MDR, decrease drug dosage, enhance patient compliance and increase efficacy. This review summarizes the current progress of CM reversal agents..
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Affiliation(s)
- Huan-Dong Zhao
- Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, China.,School of Pharmacy, Central South University, Changsha, 410013, China
| | - Hong-Juan Xie
- Department of Pharmacy, Tongren Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200336, China
| | - Jian Li
- Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Cai-Ping Ren
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, 410078, China
| | - Yu-Xiang Chen
- School of Pharmacy, Central South University, Changsha, 410013, China.
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21
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Gao Y, Shi W, Cui J, Liu C, Bi X, Li Z, Huang W, Wang G, Qian H. Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors. Bioorg Med Chem 2018; 26:2420-2427. [DOI: 10.1016/j.bmc.2018.03.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/27/2018] [Accepted: 03/31/2018] [Indexed: 01/18/2023]
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22
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AP-2α reverses vincristine-induced multidrug resistance of SGC7901 gastric cancer cells by inhibiting the Notch pathway. Apoptosis 2018; 22:933-941. [PMID: 28439677 DOI: 10.1007/s10495-017-1379-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Multidrug resistance (MDR) remains a major clinical obstacle in the treatment of gastric cancer (GC) since it causes tumor recurrence and metastasis. The transcription factor activator protein-2α (AP-2α) has been implicated in drug-resistance in breast cancer; however, its effects on MDR of gastric cancer are far from understood. In this study, we aimed to explore the effects of AP-2α on the MDR in gastric cancer cells selected by vincristine (VCR). Decreased AP-2α levels were markedly detected by RT-PCR and Western blot in gastric cancer cell lines (BGC-823, SGC-7901, AGS, MKN-45) compared with that in the gastric epithelial cell line (GES-1). Furthermore, we found that the expression of AP-2α in SGC7901/VCR or SGC7901/adriamycin (ADR) cells was lower than in SGC7901 cells. Thus, a vector overexpressing AP-2α was constructed and used to perform AP-2α gain-of-function studies in SGC7901/VCR cells. The decreased IC50 values of the anti-cancer drugs in sensitive and resistant cells after transfect with pcDNA3.1/AP-2α were determined in SGC7901/VCR cells by MTT assay. Moreover, flow cytometry analysis indicated that overexpressed AP-2α induced cell cycle arrest in the G0/G1 phase and promoted cell apoptosis of VCR-selected SGC7901/VCR cells. RT-PCR and Western blot demonstrated that overexpressed AP-2α can significantly induce the down-regulation of Notch1, Hes-1, P-gp and MRP1 in SGC7901/VCR cells. Similar effects can be observed when Numb (Notch inhibitor) was introduced. In addition, the intracellular ADR accumulation was markedly detected in AP-2α overexpressed or Numb cells. In conclusion, our results indicate that AP-2α can reverse the MDR of gastric cancer cells, which may be realized by inhibiting the Notch signaling pathway.
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Shen J, Zeng L, Pan L, Yuan S, Wu M, Kong X. Tetramethylpyrazine regulates breast cancer cell viability, migration, invasion and apoptosis by affecting the activity of Akt and caspase-3. Oncol Lett 2018. [PMID: 29541225 DOI: 10.3892/ol.2018.7851] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Tetramethylpyrazine (TMP), an effective component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in a number of types of malignant epithelial cancer. However, the mode of action of TMP on breast cancer cells remains unknown. The aim of the present study was to investigate the regulatory effect of TMP on breast cancer cells and its underlying molecular mechanism of action. Different concentrations of TMP were used to treat breast cancer cells, and subsequently, the effects on the viability, apoptosis, and migration and invasion abilities were determined. In addition, the expression and activity levels of the protein kinase B (Akt) signaling pathway and caspase-3 were explored via reverse transcription-quantitative polymerase chain reaction and western blot analysis. The results of the present study revealed that TMP significantly inhibited the viability, migration and invasion rates, and increased the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The minimum effective dose was ~1,600 µM. Additional mechanistic studies demonstrated that 1,600 and 3,200 µM TMP significantly decreased the gene expression and activity of Akt and increased the activity of caspase-3. This mechanism may be responsible for the inhibition of viability, migration and invasion, and activation of apoptosis in breast cancer cells. The results of the present study suggested that TMP may be used in chemotherapy against breast cancer.
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Affiliation(s)
- Jianliang Shen
- Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, P.R. China
| | - Linwen Zeng
- Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, P.R. China
| | - Liangming Pan
- Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, P.R. China
| | - Shaofeng Yuan
- Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, P.R. China
| | - Ming Wu
- Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, P.R. China
| | - Xiongdong Kong
- Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, P.R. China
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