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Hua W, Li F, Yang P, Lu Z, Liu Y, Zhong B, Shen B. Resveratrol derivative modified Ru(II) complexes: Synthesis, characterization, in vitro and in vivo anticancer study. J Inorg Biochem 2025; 267:112873. [PMID: 40048805 DOI: 10.1016/j.jinorgbio.2025.112873] [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: 12/02/2024] [Revised: 02/18/2025] [Accepted: 02/25/2025] [Indexed: 03/15/2025]
Abstract
The diversification of ligands provides more opportunities to adjust the photophysical performance as well as the bio-function of Ru(II) complexes as novel photosensitizers. Herein, a kind of Ru(II) complexes carrying resveratrol derivative, amino-Res, as ligand was designed and synthesized. The representative complex (named Ru4) showed potent anticancer activity under the trigger of 520 nm-light. Lipophilicity and cellular accumulation experiments indicated that Ru4 possessed higher LogPO/W value and cell up-take than Ru1-Ru3 and [Ru(bpy)3]2+. Mechanism study revealed that Ru4 could inhibit cancer cell migration, invasion and cancer stemness. The bio-function of Ru4 was mainly inherited from the amino-Res ligand. The in vivo study demonstrated that Ru4 could inhibit the tumor growth without significant system toxicity.
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Affiliation(s)
- Wuyang Hua
- School of Food Science and Nutrition Engineering, Jilin Agricultural Science and Technology University, 77(th) Han Lin Road, Jilin City 132101, China; Jilin Province Brewing Technology Science and Technology Innovation Center, 77(th) Han Lin Road, Jilin City 132101, China.
| | - Fenglin Li
- School of Food Science and Nutrition Engineering, Jilin Agricultural Science and Technology University, 77(th) Han Lin Road, Jilin City 132101, China; Jilin Province Brewing Technology Science and Technology Innovation Center, 77(th) Han Lin Road, Jilin City 132101, China
| | - Ping Yang
- School of Food Science and Nutrition Engineering, Jilin Agricultural Science and Technology University, 77(th) Han Lin Road, Jilin City 132101, China; Jilin Province Brewing Technology Science and Technology Innovation Center, 77(th) Han Lin Road, Jilin City 132101, China
| | - Zhongkui Lu
- School of Food Science and Nutrition Engineering, Jilin Agricultural Science and Technology University, 77(th) Han Lin Road, Jilin City 132101, China; Jilin Province Brewing Technology Science and Technology Innovation Center, 77(th) Han Lin Road, Jilin City 132101, China
| | - Yanxia Liu
- School of Food Science and Nutrition Engineering, Jilin Agricultural Science and Technology University, 77(th) Han Lin Road, Jilin City 132101, China; Jilin Province Brewing Technology Science and Technology Innovation Center, 77(th) Han Lin Road, Jilin City 132101, China
| | - Bao Zhong
- School of Food Science and Nutrition Engineering, Jilin Agricultural Science and Technology University, 77(th) Han Lin Road, Jilin City 132101, China; Jilin Province Brewing Technology Science and Technology Innovation Center, 77(th) Han Lin Road, Jilin City 132101, China
| | - Baoxing Shen
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, 2(nd) Xue Lin Road, Nanjing 210023, China.
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Cai W, Li Z, Wang W, Liu S, Li Y, Sun X, Sutton R, Deng L, Liu T, Xia Q, Huang W. Resveratrol in animal models of pancreatitis and pancreatic cancer: A systematic review with machine learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156538. [PMID: 40037107 DOI: 10.1016/j.phymed.2025.156538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 12/27/2024] [Accepted: 02/16/2025] [Indexed: 03/06/2025]
Abstract
BACKGROUND Resveratrol (RES), a common type of plant polyphenols, has demonstrated promising therapeutic efficacy and safety in animal models of pancreatitis and pancreatic cancer. However, a comprehensive analysis of these data is currently unavailable. This study aimed to systematically review the preclinical evidence regarding RES's effects on animal models of pancreatitis and pancreatic cancer via meta-analyses and optimised machine learning techniques. METHODS Animal studies published from inception until June 30th 2024, were systematically retrieved and manually filtrated across databases including PubMed, EMBASE, Web of Science, Ovid MEDLINE, Scopus, and Cochrane Library. Methodological quality of the included studies was evaluated following the SYRCLE's RoB tool. Predefined outcomes included histopathology and relevant biochemical parameters for acute pancreatitis, and tumour weight/tumour volume for pancreatic cancer, comparing treatment and model groups. Pooled effect sizes of the outcomes were calculated using STATA 17.0 software. Machine learning techniques were employed to predict the optimal usage and dosage of RES in pancreatitis models. RESULTS A total of 50 studies comprising 33 for acute pancreatitis, 1 chronic pancreatitis, and 16 for pancreatic cancer were included for data synthesis after screening 996 records. RES demonstrated significant improvements on pancreatic histopathology score, pancreatic function parameters (serum amylase and lipase), inflammatory markers (TNF-α, IL-1β, IL-6, and pancreatic myeloperoxidase), oxidative biomarkers (malondialdehyde and superoxide dismutase), and lung injury (lung histopathology and myeloperoxidase) in acute pancreatitis models. In pancreatic cancer models, RES notably reduced tumour weight and volume. Machine learning highlighted tree-structured Parzen estimator-optimised gradient boosted decision tree model as achieving the best performance, identifying course after disease induction, total dosage, single dosage, and total number of doses as critical factors for improving pancreatic histology. Optimal single dosage was 20-105 mg/kg with 3 to 9 doses. CONCLUSION This study comprehensively demonstrates the therapeutic effects of RES in mitigating pancreatitis and pancreatic cancer in animal models. Anti-inflammatory, anti-oxidative, and anti-tumour growth properties are potential mechanisms of action for RES.
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Affiliation(s)
- Wenhao Cai
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ziyu Li
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wen Wang
- Chinese Evidence-based Medicine and Cochrane China Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shiyu Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuying Li
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xin Sun
- Chinese Evidence-based Medicine and Cochrane China Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Robert Sutton
- Liverpool Pancreatitis Research Group, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Lihui Deng
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tingting Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Qing Xia
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Wei Huang
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China.
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Sahu SK, Prabhakar PK, Vyas M. Therapeutical potential of natural products in treatment of pancreatic cancer: a review. Mol Biol Rep 2025; 52:179. [PMID: 39888508 DOI: 10.1007/s11033-025-10287-8] [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: 10/10/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
Pancreatic cancer remains as global health challenge, ranking as the seventh leading cause of cancer-related deaths worldwide with high mortality rates and a low five-year survival rate. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiation, the overall survival rates for pancreatic cancer patients have shown minimal improvement. Consequently, there is an urgent need for alternative therapeutic strategies. The search for effective treatments has increasingly turned towards natural products, which offer a diverse array of bioactive compounds with potential anticancer properties. All the natural products, derived from plants, marine organisms, and microorganisms, have emerged as promising candidates in cancer treatment. The review explores the potential role of various natural compounds such as polyphenols, alkaloids, terpenoids, and flavonoids in pancreatic cancer management. With over 60% of cancer medications in clinical trials having natural origins, the review underscores the importance of exploring these compounds for their chemopreventive potential. It covers the epidemiological, molecular pathways influenced by these natural products (such as apoptosis, cell cycle regulation and signaling pathways) and therapeutic aspects aims to contribute to the ongoing efforts in understanding and addressing the complexities of pancreatic cancer. Overall, this review highlights the urgency of developing novel therapeutic strategies and incorporating natural compounds into current treatment modalities to improve outcomes for pancreatic cancer patients.
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Affiliation(s)
- Sanjeev Kumar Sahu
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India.
| | - Pranav Kumar Prabhakar
- Research and Development Cell, Parul University, P.O. Limda, Dist. Vadodara, Ta.Waghodia, Gujarat, 391760, India
| | - Manish Vyas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
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Rajendran P, Renu K, Ali EM, Genena MAM, Veeraraghavan V, Sekar R, Sekar AK, Tejavat S, Barik P, Abdallah BM. Promising and challenging phytochemicals targeting LC3 mediated autophagy signaling in cancer therapy. Immun Inflamm Dis 2024; 12:e70041. [PMID: 39436197 PMCID: PMC11494898 DOI: 10.1002/iid3.70041] [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: 05/28/2024] [Revised: 09/21/2024] [Accepted: 10/01/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Phytochemicals possess a wide range of anti-tumor properties, including the modulation of autophagy and regulation of programmed cell death. Autophagy is a critical process in cellular homeostasis and its dysregulation is associated with several pathological conditions, such as cancer, neurodegenerative diseases, and diabetes. In cancer, autophagy plays a dual role by either promoting tumor growth or suppressing it, depending on the cellular context. During autophagy, autophagosomes engulf cytoplasmic components such as proteins and organelles. LC3-II (microtubule-associated protein 1 light chain 3-II) is an established marker of autophagosome formation, making it central to autophagy monitoring in mammals. OBJECTIVE To explore the regulatory role of phytochemicals in LC3-mediated autophagy and their potential therapeutic impact on cancer. The review emphasizes the involvement of autophagy in tumor promotion and suppression, particularly focusing on autophagy-related signaling pathways like oxidative stress through the NRF2 pathway, and its implications for genomic stability in cancer development. METHODS The review focuses on a comprehensive analysis of bioactive compounds including Curcumin, Celastrol, Resveratrol, Kaempferol, Naringenin, Carvacrol, Farnesol, and Piperine. Literature on these compounds was examined to assess their influence on autophagy, LC3 expression, and tumor-related signaling pathways. A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to 2023. Studies were selected from prominent databases, focusing on their roles in cancer diagnosis and therapeutic interventions, particularly in relation to LC3-mediated mechanisms. RESULTS Phytochemicals have been shown to modulate autophagy through the regulation of LC3-II levels and autophagic flux in cancer cells. The interaction between autophagy and other cellular pathways such as oxidative stress, inflammation, and epigenetic modulation highlights the complex role of autophagy in tumor biology. For instance, Curcumin and Resveratrol have been reported to either induce or inhibit autophagy depending on cancer type, influencing tumor progression and therapeutic responses. CONCLUSION Targeting autophagy through LC3 modulation presents a promising strategy for cancer therapy. The dual role of autophagy in tumor suppression and promotion, however, necessitates careful consideration of the context in which autophagy is induced or inhibited. Future research should aim to delineate these context-specific roles and explore how phytochemicals can be optimized for therapeutic efficacy. Novel therapeutic strategies should focus on the use of bioactive compounds to fine-tune autophagy, thereby maximizing tumor suppression and inducing programmed cell death in cancer cells.
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Affiliation(s)
- Peramaiyan Rajendran
- Department of Biological Sciences, College of ScienceKing Faisal UniversityAl‐AhsaSaudi Arabia
- Department of Biochemistry, Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical SciencesSaveetha UniversityChennaiTamil NaduIndia
| | - Kaviyarasi Renu
- Department of Biochemistry, Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical SciencesSaveetha UniversityChennaiTamil NaduIndia
| | - Enas M. Ali
- Department of Biological Sciences, College of ScienceKing Faisal UniversityAl‐AhsaSaudi Arabia
- Department of Botany and Microbiology, Faculty of ScienceCairo UniversityCairoEgypt
| | - Marwa Azmy M. Genena
- Department of Biological Sciences, College of ScienceKing Faisal UniversityAl‐AhsaSaudi Arabia
- Agricultural Zoology Department, Faculty of AgricultureMansoura UniversityMansouraEgypt
| | - Vishnupriya Veeraraghavan
- Department of Biochemistry, Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical SciencesSaveetha UniversityChennaiTamil NaduIndia
| | - Ramya Sekar
- Department of Oral & Maxillofacial Pathology and Oral MicrobiologyMeenakshi Ammal Dental College & Hospital, MAHERChennaiTamil NaduIndia
| | | | - Sujatha Tejavat
- Department of Biomedical Sciences, College of MedicineKing Faisal UniversityAl‐AhsaSaudi Arabia
| | | | - Basem M. Abdallah
- Department of Biological Sciences, College of ScienceKing Faisal UniversityAl‐AhsaSaudi Arabia
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Jiang H, Wang GT, Wang Z, Ma QY, Ma ZH. Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts. World J Gastrointest Oncol 2024; 16:3980-3993. [PMID: 39350997 PMCID: PMC11438786 DOI: 10.4251/wjgo.v16.i9.3980] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 06/26/2024] [Accepted: 08/02/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Pancreatic cancer, a formidable gastrointestinal neoplasm, is characterized by its insidious onset, rapid progression, and resistance to treatment, which often lead to a grim prognosis. While the complex pathogenesis of pancreatic cancer is well recognized, recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts. However, their precise role in pancreatic cancer remains unknown. Resveratrol is a natural polyphenol known for its multifaceted biological actions, including antioxidative and neuroprotective properties, as well as its potential to inhibit tumor proliferation and migration. Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis. AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts. METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression of α-SMA and p16. HP-1 expression was determined using immunohistochemistry. Cells were treated with the senescence-inducing factors known as 3CKs. Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate. Western blotting was conducted to assess the expression levels of p16 and p21. Immunofluorescence was performed to assess LaminB1 expression. Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors, including IL-4, IL-6, IL-8, IL-13, MMP-2, MMP-9, CXCL1, and CXCL12. A scratch assay was used to assess the migratory capacity of the cells, whereas Transwell assays were used to evaluate their invasive potential. RESULTS Specifically, we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues, linking their abundance to cancer progression. Intriguingly, Resveratrol effectively eradicated these fibroblasts and hindered their senescence, which consequently impeded pancreatic cancer progression. CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.
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Affiliation(s)
- He Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Guo-Tai Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Qing-Yong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhen-Hua Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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DJALDETTI MEIR. Immunomodulatory and chemopreventive effects of resveratrol on the digestive system cancers. Oncol Res 2024; 32:1389-1399. [PMID: 39220125 PMCID: PMC11361903 DOI: 10.32604/or.2024.049745] [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: 01/17/2024] [Accepted: 05/23/2024] [Indexed: 09/04/2024] Open
Abstract
Resveratrol (RSV), the primary polyphenol found in grapes, has been revealed to have anti-inflammatory properties by reducing the capacity of the peripheral blood mononuclear cells to produce pro-inflammatory cytokines, including IL-1β, IL-6, IL-1ra and TNFα. Considering the close association between chronic inflammation and cancer development, RSV's immunomodulatory properties are one way by which the polyphenol may inhibit cancer initiation, proliferation, neovascularization, and migration. Resveratrol influences the generation of microtumor environment which is one of the key factors in cancer progress. In addition to immunomodulation, RSV inhibits cancer development by expressing anti-oxidant effects, causing cell cycle arrest, stimulating the function of certain enzymes, and activating cell signaling pathways. The end outcome is one of the various forms of cell death, including apoptosis, pyroptosis, necroptosis, and more, as it has been observed in vitro. RSV has been shown to act against cancer in practically every organ, while its effects on colon cancer have been documented more frequently. It is remarkable that longer-term clinical studies that may have established the potential for this natural substance to serve as a therapeutic adjuvant to traditional anti-cancer medications were not prompted by the encouraging outcomes seen with cancer cells treated with non-toxic doses of resveratrol. The current review aims to assess the recent findings about the immunological and anti-cancer characteristics of RSV, with a particular emphasis on cancers of the digestive tract, as a challenge for future clinical research that may contribute to the better prognosis of cancer.
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Affiliation(s)
- MEIR DJALDETTI
- />Laboratory for Immunology and Hematology Research, Rabin Medical Center, Hasharon Hospital, Petah-Tiqva, the Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Israel
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Fakhri S, Moradi SZ, Faraji F, Kooshki L, Webber K, Bishayee A. Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review. Cancer Metastasis Rev 2024; 43:501-574. [PMID: 37792223 DOI: 10.1007/s10555-023-10136-9] [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: 08/17/2023] [Accepted: 09/07/2023] [Indexed: 10/05/2023]
Abstract
Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Farahnaz Faraji
- Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Leila Kooshki
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, 6714415153, Iran
| | - Kassidy Webber
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL, 34211, USA
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL, 34211, USA.
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Li Z, Wang Q, Huang X, Fu R, Wen X, Zhang L. Multi-omics analysis reveals that ferroptosis-related gene CISD2 is a prognostic biomarker of head and neck squamous cell carcinoma. J Gene Med 2024; 26:e3580. [PMID: 37581006 DOI: 10.1002/jgm.3580] [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: 03/27/2023] [Revised: 06/24/2023] [Accepted: 07/25/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy, with high mortality rate and unavailability of accurate therapies. However, its early prevention remains a challenge. In the purview of predictive, preventive, and personalized medicine (PPPM), it is paramount to identify novel and powerful biomarkers. CISD2 is a crucial regulator of iron homeostasis and reactive oxygen species (ROS). Recent studies showed that the NEET protein (NAF-1) encoded by CISD2 is involved in regulating the proliferation and metastasis of tumor cells. Nevertheless, the prognostic value and immunological correlations of CISD2 remain unclear. METHODS Bioinformatics analyses conducted utilizing data from comprehensive databases The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). All statistical evaluations were executed employing R software. RESULTS Our investigation of biological function, enrichment pathway, and immune correlation revealed a discernable linkage between CISD2 and the immune response. Moreover, we found that the suppression of CISD2 is associated with immune cell infiltration and various immune signatures. CONCLUSIONS The present study successfully revealed the potential prognostic and biological function of CISD2 in HNSCC. High expression of CISD2 are linked to gender, race, grade, etc., can notably enhance the early detection, prognosis, and prediction for individuals afflicted with HNSCC.
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Affiliation(s)
- Zhengrui Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Research Institute of Stomatology, Shanghai, China
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Qi Wang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Xufeng Huang
- Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
| | - Rao Fu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Research Institute of Stomatology, Shanghai, China
| | - Xutao Wen
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Research Institute of Stomatology, Shanghai, China
| | - Ling Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Research Institute of Stomatology, Shanghai, China
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Anwar MJ, Altaf A, Imran M, Amir M, Alsagaby SA, Abdulmonem WA, Mujtaba A, El-Ghorab AH, Ghoneim MM, Hussain M, Jbawi EA, Shaker ME, Abdelgawad MA. Anti-cancer perspectives of resveratrol: a comprehensive review. FOOD AGR IMMUNOL 2023; 34. [DOI: 10.1080/09540105.2023.2265686] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 09/27/2023] [Indexed: 11/28/2024] Open
Affiliation(s)
- Muhammad Junaid Anwar
- Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | - Areeba Altaf
- Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | - Muhammad Imran
- Department of Food Science and Technology, University of Narowal, Narowal, Pakistan
| | - Muhammad Amir
- Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | - Suliman A. Alsagaby
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Kingdom of Saudi Arabia
| | - Ahmed Mujtaba
- Department of Food Science and Technology, Faculty of Engineering and Technology, Hamdard University Islamabad. Islamabad Campus, Islamabad, Pakistan
| | - Ahmed H. El-Ghorab
- Department of Chemistry, College of Science, Jouf University, Sakaka, Saudi Arabia
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, Saudi Arabia
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Muzzamal Hussain
- Department of Food Sciences, Government College University Faisalabad, Pakistan
| | | | - Mohamed E. Shaker
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed A. Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni suef, Egypt
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10
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Anwar MJ, Altaf A, Imran M, Amir M, Alsagaby SA, Abdulmonem WA, Mujtaba A, El-Ghorab AH, Ghoneim MM, Hussain M, Jbawi EA, Shaker ME, Abdelgawad MA. Anti-cancer perspectives of resveratrol: a comprehensive review. FOOD AGR IMMUNOL 2023; 34. [DOI: https:/doi.org/10.1080/09540105.2023.2265686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 09/27/2023] [Indexed: 05/18/2024] Open
Affiliation(s)
- Muhammad Junaid Anwar
- Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | - Areeba Altaf
- Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | - Muhammad Imran
- Department of Food Science and Technology, University of Narowal, Narowal, Pakistan
| | - Muhammad Amir
- Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | - Suliman A. Alsagaby
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Kingdom of Saudi Arabia
| | - Ahmed Mujtaba
- Department of Food Science and Technology, Faculty of Engineering and Technology, Hamdard University Islamabad. Islamabad Campus, Islamabad, Pakistan
| | - Ahmed H. El-Ghorab
- Department of Chemistry, College of Science, Jouf University, Sakaka, Saudi Arabia
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, Saudi Arabia
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Muzzamal Hussain
- Department of Food Sciences, Government College University Faisalabad, Pakistan
| | | | - Mohamed E. Shaker
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed A. Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni suef, Egypt
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11
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Liju VB, Martin S, Nath LR, Gopinadhan Nair GK, Thayele Purayil H. Editorial: Plant-based drugs: the potential novel therapeutic intervention against cancer stemness and metastasis. Front Pharmacol 2023; 14:1283694. [PMID: 37869751 PMCID: PMC10588462 DOI: 10.3389/fphar.2023.1283694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 09/29/2023] [Indexed: 10/24/2023] Open
Affiliation(s)
- Vijayasteltar B. Liju
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Sunil Martin
- Laboratory of Synthetic Immunology, Cancer Immunotherapy Program, Division of Cancer Research, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Lekshmi R. Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi Campus, Kochi, Kerala, India
| | - Gopa Kumar Gopinadhan Nair
- Department of Ophthalmology, Keck School of Medicine, USC Roski Eye Institute, University of Southern California, Los Angeles, CA, United States
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12
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Liu S, Li L, Ren D. Anti-Cancer Potential of Phytochemicals: The Regulation of the Epithelial-Mesenchymal Transition. Molecules 2023; 28:5069. [PMID: 37446730 DOI: 10.3390/molecules28135069] [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: 06/05/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
A biological process called epithelial-mesenchymal transition (EMT) allows epithelial cells to change into mesenchymal cells and acquire some cancer stem cell properties. EMT contributes significantly to the metastasis, invasion, and development of treatment resistance in cancer cells. Current research has demonstrated that phytochemicals are emerging as a potential source of safe and efficient anti-cancer medications. Phytochemicals could disrupt signaling pathways related to malignant cell metastasis and drug resistance by suppressing or reversing the EMT process. In this review, we briefly describe the pathophysiological properties and the molecular mechanisms of EMT in the progression of cancers, then summarize phytochemicals with diverse structures that could block the EMT process in different types of cancer. Hopefully, these will provide some guidance for future research on phytochemicals targeting EMT.
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Affiliation(s)
- Shuangyu Liu
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China
| | - Lingyu Li
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China
| | - Dongmei Ren
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China
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13
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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14
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Xie C, Liang C, Wang R, Yi K, Zhou X, Li X, Chen Y, Miao D, Zhong C, Zhu J. Resveratrol suppresses lung cancer by targeting cancer stem-like cells and regulating tumor microenvironment. J Nutr Biochem 2023; 112:109211. [PMID: 36370924 DOI: 10.1016/j.jnutbio.2022.109211] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 06/30/2022] [Accepted: 09/23/2022] [Indexed: 11/11/2022]
Abstract
Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound.
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Affiliation(s)
- Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chunhua Liang
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rong Wang
- State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kefan Yi
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xu Zhou
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoting Li
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yue Chen
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dengshun Miao
- Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Caiyun Zhong
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Jianyun Zhu
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
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15
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Lo Iacono M, Gaggianesi M, Bianca P, Brancato OR, Muratore G, Modica C, Roozafzay N, Shams K, Colarossi L, Colarossi C, Memeo L, Turdo A, Veschi V, Di Franco S, Todaro M, Stassi G. Destroying the Shield of Cancer Stem Cells: Natural Compounds as Promising Players in Cancer Therapy. J Clin Med 2022; 11:6996. [PMID: 36498571 PMCID: PMC9737492 DOI: 10.3390/jcm11236996] [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: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
In a scenario where eco-sustainability and a reduction in chemotherapeutic drug waste are certainly a prerogative to safeguard the biosphere, the use of natural products (NPs) represents an alternative therapeutic approach to counteract cancer diseases. The presence of a heterogeneous cancer stem cell (CSC) population within a tumor bulk is related to disease recurrence and therapy resistance. For this reason, CSC targeting presents a promising strategy for hampering cancer recurrence. Increasing evidence shows that NPs can inhibit crucial signaling pathways involved in the maintenance of CSC stemness and sensitize CSCs to standard chemotherapeutic treatments. Moreover, their limited toxicity and low costs for large-scale production could accelerate the use of NPs in clinical settings. In this review, we will summarize the most relevant studies regarding the effects of NPs derived from major natural sources, e.g., food, botanical, and marine species, on CSCs, elucidating their use in pre-clinical and clinical studies.
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Affiliation(s)
- Melania Lo Iacono
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Paola Bianca
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Ornella Roberta Brancato
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Giampaolo Muratore
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Chiara Modica
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Narges Roozafzay
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Kimiya Shams
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Lorenzo Colarossi
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Cristina Colarossi
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Alice Turdo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
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16
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Troumpoukis D, Papadimitropoulou A, Charalampous C, Kogionou P, Palamaris K, Sarantis P, Serafimidis I. Targeting autophagy in pancreatic cancer: The cancer stem cell perspective. Front Oncol 2022; 12:1049436. [PMID: 36505808 PMCID: PMC9730023 DOI: 10.3389/fonc.2022.1049436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is currently the seventh leading cause of cancer-related deaths worldwide, with the estimated death toll approaching half a million annually. Pancreatic ductal adenocarcinoma (PDAC) is the most common (>90% of cases) and most aggressive form of pancreatic cancer, with extremely poor prognosis and very low survival rates. PDAC is initiated by genetic alterations, usually in the oncogene KRAS and tumor suppressors CDKN2A, TP53 and SMAD4, which in turn affect a number of downstream signaling pathways that regulate important cellular processes. One of the processes critically altered is autophagy, the mechanism by which cells clear away and recycle impaired or dysfunctional organelles, protein aggregates and other unwanted components, in order to achieve homeostasis. Autophagy plays conflicting roles in PDAC and has been shown to act both as a positive effector, promoting the survival of pancreatic tumor-initiating cells, and as a negative effector, increasing cytotoxicity in uncontrollably expanding cells. Recent findings have highlighted the importance of cancer stem cells in PDAC initiation, progression and metastasis. Pancreatic cancer stem cells (PaCSCs) comprise a small subpopulation of the pancreatic tumor, characterized by cellular plasticity and the ability to self-renew, and autophagy has been recognised as a key process in PaCSC maintenance and function, simultaneously suggesting new strategies to achieve their selective elimination. In this review we evaluate recent literature that links autophagy with PaCSCs and PDAC, focusing our discussion on the therapeutic implications of pharmacologically targeting autophagy in PaCSCs, as a means to treat PDAC.
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Affiliation(s)
- Dimitrios Troumpoukis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | | | - Chrysanthi Charalampous
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Paraskevi Kogionou
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Serafimidis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece,*Correspondence: Ioannis Serafimidis,
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17
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Li N, Li C, Zhang J, Jiang Q, Wang Z, Nie S, Gao Z, Li G, Fang H, Ren S, Li X. Discovery of semisynthetic celastrol derivatives exhibiting potent anti-ovarian cancer stem cell activity and STAT3 inhibition. Chem Biol Interact 2022; 366:110172. [PMID: 36096161 DOI: 10.1016/j.cbi.2022.110172] [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: 07/25/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 11/03/2022]
Abstract
The hallmark of ovarian cancer is its high mortality rate attributed to the existence of cancer stem cells (CSCs) subpopulations which result in therapy recurrence and metastasis. A series of C-29-substituted and/or different A/B ring of celastrol derivatives were synthesized and displayed potential inhibition against ovarian cancer cells SKOV3, A2780 and OVCAR3. Among them, compound 6c exhibited the most potent anti-proliferative activity and selectivity, gave superior anti-CSC effects through inhibition of the sphere formation and downregulation of the percentage of CD44+CD24- and ALDH+ cells. Further mechanism research demonstrated that compound 6c could attenuate the expression of STAT3 and p-STAT3. The results suggested that the inhibition of celastrol derivative 6c on ovarian cancer cells may be related to resistance to cancer stem-like characters and regulation of STAT3 pathway.
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Affiliation(s)
- Na Li
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Chaobo Li
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Juan Zhang
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Qian Jiang
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Zhaoxue Wang
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Shaozhen Nie
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Zhenzhen Gao
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China
| | - Guangyao Li
- Central Laboratory, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, PR China
| | - Hao Fang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
| | - Shaoda Ren
- Central Laboratory, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, PR China.
| | - Xiaojing Li
- Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
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18
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Periplocin Induces Apoptosis of Pancreatic Cancer Cells through Autophagy via the AMPK/mTOR Pathway. JOURNAL OF ONCOLOGY 2022; 2022:8055004. [PMID: 35847371 PMCID: PMC9277210 DOI: 10.1155/2022/8055004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/24/2022] [Accepted: 06/04/2022] [Indexed: 11/30/2022]
Abstract
Periplocin, a natural compound, has been shown to induce apoptosis in a variety of cancer cells. However, no research has been conducted to demonstrate that Periplocin has a regulatory effect on autophagy. This study is aimed to determine the effect of Periplocin treatment on autophagy in human pancreatic cancer cells, as well as the underlying mechanisms. Pancreatic cancer cells were treated with different concentrations of Periplocin, and real-time cell analysis (RTCA), colony formation assay, and Ki67 immunofluorescence detection were used to determine cell proliferation. Autophagy protein was detected by immunofluorescence and western blotting. Western blotting was also used to detect the caspase family of apoptotic proteins. Flow cytometry and TUNEL staining were used to detect cell apoptosis. Following treatment with Periplocin, the expression of autophagy genes was detected using RNA-seq. In vivo examination of the effect of Periplocin on autophagy in pancreatic was performed using a xenograft model. Periplocin inhibits the proliferation of CFPAC1 and PANC1 cells and induces autophagy by regulating the AMPK/mTOR pathway. Using the AMPK inhibitor Compound C(CC), both the Periplocin-induced inhibition of cell proliferation and autophagy activation was reduced, which further verified this conclusion. Periplocin inhibits CFPAC1 xenograft tumor growth in nude mice and increases tumor cell autophagy. Collectively, these results have shown that Periplocin promotes autophagy in human pancreatic cancer cells by regulating the AMPK/mTOR pathway.
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19
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Roshani M, Jafari A, Loghman A, Sheida AH, Taghavi T, Tamehri Zadeh SS, Hamblin MR, Homayounfal M, Mirzaei H. Applications of resveratrol in the treatment of gastrointestinal cancer. Biomed Pharmacother 2022; 153:113274. [PMID: 35724505 DOI: 10.1016/j.biopha.2022.113274] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/28/2022] [Accepted: 06/08/2022] [Indexed: 12/15/2022] Open
Abstract
Natural product compounds have lately attracted interest in the scientific community as a possible treatment for gastrointestinal (GI) cancer, due to their anti-inflammatory and anticancer properties. There are many preclinical, clinical, and epidemiological studies, suggesting that the consumption of polyphenol compounds, which are abundant in vegetables, grains, fruits, and pulses, may help to prevent various illnesses and disorders from developing, including several GI cancers. The development of GI malignancies follows a well-known path, in which normal gastrointestinal cells acquire abnormalities in their genetic composition, causing the cells to continuously proliferate, and metastasize to other sites, especially the brain and liver. Natural compounds with the ability to affect oncogenic pathways might be possible treatments for GI malignancies, and could easily be tested in clinical trials. Resveratrol is a non-flavonoid polyphenol and a natural stilbene, acting as a phytoestrogen with anti-cancer, cardioprotective, anti-oxidant, and anti-inflammatory properties. Resveratrol has been shown to overcome resistance mechanisms in cancer cells, and when combined with conventional anticancer drugs, could sensitize cancer cells to chemotherapy. Several new resveratrol analogs and nanostructured delivery vehicles with improved anti-GI cancer efficacy, absorption, and pharmacokinetic profiles have already been developed. This present review focuses on the in vitro and in vivo effects of resveratrol on GI cancers, as well as the underlying molecular mechanisms of action.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ameneh Jafari
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran; Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amir Hossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | | | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Mina Homayounfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Celastrol and Resveratrol Modulate SIRT Genes Expression and Exert Anticancer Activity in Colon Cancer Cells and Cancer Stem-like Cells. Cancers (Basel) 2022; 14:cancers14061372. [PMID: 35326523 PMCID: PMC8945991 DOI: 10.3390/cancers14061372] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/24/2022] [Accepted: 03/06/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The recovery rate in patients with metastatic colorectal cancer (CRC) remains low and declines with successive lines of treatment. This phenomenon is caused by the development of drug resistance and the presence of colorectal cancer stem cells (CSCs). Phytochemicals, like -celastrol and resveratrol, are very promising for colon cancer therapy, owing to their low or no toxicity and their pleiotropic activity, enabling them to interact with various biological targets. In the present study, the potential anticancer mechanisms of both compounds against metastatic colon cancer cells and the capacity to eradicate CSCs were investigated. Abstract Metastatic colorectal cancer (CRC) remains a hard-to-cure neoplasm worldwide. Its curability declines with successive lines of treatment due to the development of various cancer resistance mechanisms and the presence of colorectal cancer stem cells (CSCs). Celastrol and resveratrol are very promising phytochemicals for colon cancer therapy, owing to their pleiotropic activity that enables them to interact with various biological targets. In the present study, the anticancer activities of both compounds were investigated in metastatic colon cancer cells (LoVo cells) and cancer stem-like cells (LoVo/DX). We showed that celastrol is a very potent anti-tumor compound against metastatic colon cancer, capable of attenuating CSC-like cells at the molecular and cellular levels. In contrast, resveratrol has a much greater effect on colon cancer cells that are expressing standard sensitivity to anticancer drugs, than on CSC-like cells. In addition, both polyphenols have different influences on the expression of SIRT genes, which seems to be at least partly related to their anti-tumor activity.
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Alhusaini AM, Fadda LM, Alanazi AM, Sarawi WS, Alomar HA, Ali HM, Hasan IH, Ali RA. Nano-Resveratrol: A Promising Candidate for the Treatment of Renal Toxicity Induced by Doxorubicin in Rats Through Modulation of Beclin-1 and mTOR. Front Pharmacol 2022; 13:826908. [PMID: 35281939 PMCID: PMC8913579 DOI: 10.3389/fphar.2022.826908] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/17/2022] [Indexed: 12/30/2022] Open
Abstract
Background: Although doxorubicin (DXR) is one of the most used anticancer drugs, it can cause life-threatening renal damage. There has been no effective treatment for DXR-induced renal damage until now. Aim: This work aims at examining the potential impact of nano-resveratrol (N-Resv), native resveratrol (Resv), and their combination with carvedilol (Card) against DXR-induced renal toxicity in rats and to investigate the mechanisms through which these antioxidants act to ameliorate DXR nephrotoxicity. Method: DXR was administered to rats (2 mg/kg, i.p.) twice weekly over 5 weeks. The antioxidants in question were taken 1 week before the DXR dose for 6 weeks. Results: DXR exhibited an elevation in serum urea, creatinine, renal lipid peroxide levels, endoglin expression, kidney injury molecule-1 (KIM-1), and beclin-1. On the other hand, renal podocin and mTOR expression and GSH levels were declined. In addition, DNA fragmentation was markedly increased in the DXR-administered group. Treatment with either Resv or N-Resv alone or in combination with Card ameliorated the previously measured parameters. Conclusion: N-Resv showed superior effectiveness relative to Resv in most of the measured parameters. Histopathological examination revealed amelioration of renal structural and cellular changes after DXR by Card and N-Resv, thus validating the previous biochemical and molecular results.
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Affiliation(s)
- Ahlam M. Alhusaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- *Correspondence: Ahlam M. Alhusaini,
| | - Laila M. Fadda
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abeer M. Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Wedad S. Sarawi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hatun A. Alomar
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hanaa M. Ali
- Genetics and Cytology Department, National Research Centre, Cairo, Egypt
| | - Iman H. Hasan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Rehab Ahmed Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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22
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Silencing NAF-1 represses the proliferation and motility of PDAC cells through inhibiting HIF-1α. APPLIED NANOSCIENCE 2022. [DOI: 10.1007/s13204-022-02360-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Muñoz-López S, Sánchez-Melgar A, Martín M, Albasanz JL. Resveratrol enhances A 1 and hinders A 2A adenosine receptors signaling in both HeLa and SH-SY5Y cells: Potential mechanism of its antitumoral action. Front Endocrinol (Lausanne) 2022; 13:1007801. [PMID: 36407311 PMCID: PMC9669387 DOI: 10.3389/fendo.2022.1007801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Despite great efforts, effective treatment against cancer has not yet been found. However, natural compounds such as the polyphenol resveratrol have emerged as promising preventive agent in cancer therapy. The mode of action of resveratrol is still poorly understood, but it can modulate many signaling pathways related to the initiation and progression of cancer. Adenosinergic signaling may be involved in the antitumoral action of resveratrol since resveratrol binds to the orthosteric binding site of adenosine A2A receptors and acts as a non-selective agonist for adenosine receptors. In the present study, we measured the impact of resveratrol treatment on different adenosinergic pathway components (i.e. adenosine receptors levels, 5'-nucleotidase, adenosine deaminase, and adenylyl cyclase activities, protein kinase A levels, intracellular adenosine and other related metabolites levels) and cell viability and proliferation in HeLa and SH-SY5Y cell lines. Results revealed changes leading to turning off cAMP signaling such as decreased levels of A2A receptors and reduced adenylyl cyclase activation, increased levels of A1 receptors and increased adenylyl cyclase inhibition, and lower levels of PKA. All these changes could contribute to the antitumoral action of resveratrol. Interestingly, these effects were almost identical in HeLa and SH-SY5Y cells suggesting that resveratrol enhances A1 and hinders A2A adenosine receptors signaling as part of a potential mechanism of antitumoral action.
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Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies. Int J Mol Sci 2021; 22:ijms222111669. [PMID: 34769099 PMCID: PMC8584029 DOI: 10.3390/ijms222111669] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/23/2021] [Accepted: 10/23/2021] [Indexed: 02/07/2023] Open
Abstract
As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.
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Brimson JM, Prasanth MI, Malar DS, Thitilertdecha P, Kabra A, Tencomnao T, Prasansuklab A. Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases. Pharmaceuticals (Basel) 2021; 14:ph14100982. [PMID: 34681206 PMCID: PMC8538309 DOI: 10.3390/ph14100982] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/13/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Polyphenols are a family of naturally occurring organic compounds, majorly present in fruits, vegetables, and cereals, characterised by multiple phenol units, including flavonoids, tannic acid, and ellagitannin. Some well-known polyphenols include resveratrol, quercetin, curcumin, epigallocatechin gallate, catechin, hesperetin, cyanidin, procyanidin, caffeic acid, and genistein. They can modulate different pathways inside the host, thereby inducing various health benefits. Autophagy is a conserved process that maintains cellular homeostasis by clearing the damaged cellular components and balancing cellular survival and overall health. Polyphenols could maintain autophagic equilibrium, thereby providing various health benefits in mediating neuroprotection and exhibiting anticancer and antidiabetic properties. They could limit brain damage by dismantling misfolded proteins and dysfunctional mitochondria, thereby activating autophagy and eliciting neuroprotection. An anticarcinogenic mechanism is stimulated by modulating canonical and non-canonical signalling pathways. Polyphenols could also decrease insulin resistance and inhibit loss of pancreatic islet β-cell mass and function from inducing antidiabetic activity. Polyphenols are usually included in the diet and may not cause significant side effects that could be effectively used to prevent and treat major diseases and ailments.
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Affiliation(s)
- James Michael Brimson
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (J.M.B.); (M.I.P.); (D.S.M.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Mani Iyer Prasanth
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (J.M.B.); (M.I.P.); (D.S.M.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Dicson Sheeja Malar
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (J.M.B.); (M.I.P.); (D.S.M.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Premrutai Thitilertdecha
- Siriraj Research Group in Immunobiology and Therapeutic Sciences, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10330, Thailand;
| | - Atul Kabra
- Department of Pharmacology, University Institute of Pharma Sciences, Chandigarh University, Sahibzad Ajit Singh Nagar 140413, Punjab, India;
| | - Tewin Tencomnao
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (J.M.B.); (M.I.P.); (D.S.M.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: (T.T.); (A.P.)
| | - Anchalee Prasansuklab
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (J.M.B.); (M.I.P.); (D.S.M.)
- College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: (T.T.); (A.P.)
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Chen S, Wang W, Tan HY, Lu Y, Li Z, Qu Y, Wang N, Wang D. Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action. Front Cell Dev Biol 2021; 9:715200. [PMID: 34414192 PMCID: PMC8369482 DOI: 10.3389/fcell.2021.715200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/15/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy is an intracellular scavenging mechanism induced to eliminate damaged, denatured, or senescent macromolecular substances and organelles in the body. The regulation of autophagy plays essential roles in the processes of cellular homeostasis and senescence. Dysregulated autophagy is a common feature of several human diseases, including cancers and neurodegenerative disorders. The initiation and development of these disorders have been shown to be associated with the maintenance of disease-specific stem cell compartments. In this review, we summarize recent advances in our understanding of the role of autophagy in the maintenance of stemness. Specifically, we focus on the intersection between autophagy and adult stem cells in the initiation and progression of specific diseases. Accordingly, this review highlights the role of autophagy in stemness maintenance from the perspective of disease-associated mechanisms, which may be fundamental to our understanding of the pathogeneses of human diseases and the development of effective therapies.
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Affiliation(s)
- Shanshan Chen
- School of Life Sciences, Jilin University, Changchun, China
| | - Wenqi Wang
- School of Life Sciences, Jilin University, Changchun, China
| | - Hor-Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiping Li
- School of Life Sciences, Jilin University, Changchun, China
| | - Yidi Qu
- School of Life Sciences, Jilin University, Changchun, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun, China.,Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun, China
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Targeting cancer stem cells by nutraceuticals for cancer therapy. Semin Cancer Biol 2021; 85:234-245. [PMID: 34273521 DOI: 10.1016/j.semcancer.2021.07.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.
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Guo K, Feng Y, Zheng X, Sun L, Wasan HS, Ruan S, Shen M. Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors. Front Oncol 2021; 11:644134. [PMID: 33937049 PMCID: PMC8085503 DOI: 10.3389/fonc.2021.644134] [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: 12/20/2020] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT), a complicated program through which polarized epithelial cells acquire motile mesothelial traits, is regulated by tumor microenvironment. EMT is involved in tumor progression, invasion and metastasis via reconstructing the cytoskeleton and degrading the tumor basement membrane. Accumulating evidence shows that resveratrol, as a non-flavonoid polyphenol, can reverse EMT and inhibit invasion and migration of human tumors via diverse mechanisms and signaling pathways. In the present review, we will summarize the detailed mechanisms and pathways by which resveratrol and its analogs (e.g. Triacetyl resveratrol, 3,5,4'-Trimethoxystilbene) might regulate the EMT process in cancer cells to better understand their potential as novel anti-tumor agents. Resveratrol can also reverse chemoresistance via EMT inhibition and improvement of the antiproliferative effects of conventional treatments. Therefore, resveratrol and its analogs have the potential to become novel adjunctive agents to inhibit cancer metastasis, which might be partly related to their blocking of the EMT process.
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Affiliation(s)
- Kaibo Guo
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuqian Feng
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xueer Zheng
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Leitao Sun
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Harpreet S. Wasan
- Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Shanming Ruan
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Minhe Shen
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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Fu Y, Ricciardiello F, Yang G, Qiu J, Huang H, Xiao J, Cao Z, Zhao F, Liu Y, Luo W, Chen G, You L, Chiaradonna F, Zheng L, Zhang T. The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells. Cells 2021; 10:497. [PMID: 33669111 PMCID: PMC7996512 DOI: 10.3390/cells10030497] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/16/2021] [Accepted: 02/14/2021] [Indexed: 02/06/2023] Open
Abstract
The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In recent years, many studies have shown that mitochondria play important roles in tumorigenesis and may act as chemotherapeutic targets in PC. In addition, according to recent studies, mitochondria may play important roles in the chemoresistance of PC by affecting apoptosis, metabolism, mtDNA metabolism, and mitochondrial dynamics. Interfering with some of these factors in mitochondria may improve the sensitivity of PC cells to chemotherapeutic agents, such as gemcitabine, making mitochondria promising targets for overcoming chemoresistance in PC.
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Affiliation(s)
- Yibo Fu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Francesca Ricciardiello
- Department of Biotechnology and Bioscience, University of Milano Bicocca, 20126 Milano, Italy;
| | - Gang Yang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Jiangdong Qiu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Hua Huang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Jianchun Xiao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Zhe Cao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Fangyu Zhao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Yueze Liu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Wenhao Luo
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Guangyu Chen
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Lei You
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Bioscience, University of Milano Bicocca, 20126 Milano, Italy;
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China;
| | - Taiping Zhang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
- Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Shen ZQ, Huang YL, Teng YC, Wang TW, Kao CH, Yeh CH, Tsai TF. CISD2 maintains cellular homeostasis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:118954. [PMID: 33422617 DOI: 10.1016/j.bbamcr.2021.118954] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
CDGSH Iron Sulfur Domain 2 (CISD2) is the causative gene for the disease Wolfram syndrome 2 (WFS2; MIM 604928), which is an autosomal recessive disorder showing metabolic and neurodegenerative manifestations. CISD2 protein can be localized on the endoplasmic reticulum (ER), outer mitochondrial membrane (OMM) and mitochondria-associated membrane (MAM). CISD2 plays a crucial role in the regulation of cytosolic Ca2+ homeostasis, ER integrity and mitochondrial function. Here we summarize the most updated publications and discuss the central role of CISD2 in maintaining cellular homeostasis. This review mainly focuses on the following topics. Firstly, that CISD2 has been recognized as a prolongevity gene and the level of CISD2 is a key determinant of lifespan and healthspan. In mice, Cisd2 deficiency shortens lifespan and accelerates aging. Conversely, a persistently high level of Cisd2 promotes longevity. Intriguingly, exercise stimulates Cisd2 gene expression and thus, the beneficial effects offered by exercise may be partly related to Cisd2 activation. Secondly, that Cisd2 is down-regulated in a variety of tissues and organs during natural aging. Three potential mechanisms that may mediate the age-dependent decrease of Cisd2, via regulating at different levels of gene expression, are discussed. Thirdly, the relationship between CISD2 and cell survival, as well as the potential mechanisms underlying the cell death control, are discussed. Finally we discuss that, in cancers, CISD2 may functions as a double-edged sword, either suppressing or promoting cancer development. This review highlights the importance of the CISD2 in aging and age-related diseases and identifies the urgent need for the translation of available genetic evidence into pharmaceutic interventions in order to alleviate age-related disorders and extend a healthy lifespan in humans.
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Affiliation(s)
- Zhao-Qing Shen
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Long Huang
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Yuan-Chi Teng
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Tai-Wen Wang
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Heng Kao
- Center of General Education, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Hsiao Yeh
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linko, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan.
| | - Ting-Fen Tsai
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
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Xiong L, Lin XM, Nie JH, Ye HS, Liu J. Resveratrol and its Nanoparticle suppress Doxorubicin/Docetaxel-resistant anaplastic Thyroid Cancer Cells in vitro and in vivo. Nanotheranostics 2021; 5:143-154. [PMID: 33457193 PMCID: PMC7806457 DOI: 10.7150/ntno.53844] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/01/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Docetaxel and doxorubicin combination has been widely used in anaplastic thyroid cancer/ATC treatment but often results in serious adverse effects and drug resistance. Resveratrol effectively inhibits ATC cell proliferation in vitro without affecting the corresponding normal cells, while its in vivo anti-ATC effects especially on the ones with docetaxel/doxorubicin-resistance have not been reported due to its low bioavailability. Nanoparticles with sustained-release and cancer-targeting features may overcome this therapeutic bottleneck. Methods: The resveratrol nanoparticles with sustained-release and IL-13Rα2-targeting capacities (Pep-1-PEG3.5k-PCL4k@Res) were prepared to improve the in vivo resveratrol bioavailability. Human THJ-16T ATC cell line was employed to establish nude mice subcutaneous transplantation model. The tumor-bearing mice were divided into four groups as Group-1, without treatment, Group-2, treated by 30 mg/kg free resveratrol, Group-3, treated by 30 mg/kg Pep-1-PEG3.5k-PCL4k@Res and Group-4, treated by 5 mg/kg docetaxel/5 mg/kg doxorubicin combination. TUNEL staining was used to detect the apoptotic cells in the tumor tissues. Docetaxel/doxorubicin resistant xenografts named as THJ-16T/R were isolated and subjected to 2D and 3D culture. The docetaxel/doxorubicin and resveratrol sensitivities of the original THJ-16T and THJ-16T/R cells were analyzed by multiple methods. Results: Docetaxel/doxorubicin and Pep-1-PEG3.5k-PCL4k@Res but not free resveratrol significantly delayed tumor growth (P < 0.01) and caused extensive apoptosis. The mice in docetaxel/doxorubicin-treated group suffered from weight loss (> 10%) and 2/3 of them died within 3 times of treatment and the chemotherapy was stop to avoid further animal loss. One week after drug withdrawal, the subcutaneous tumors regrew and the tumor volume increased 55.28% within 14 days. The cells isolated from the regrowing tumors (THJ-16T/R) were successfully cultured under 2D and 3D condition and underwent drug treatments. Compared with THJ-16T, the death rate of docetaxel/doxorubicin-treated THJ-16T/R population was lower (39.3% vs 18.0%), which remained almost unchanged in resveratrol-treated group (45.3% vs 49.3%). Conclusion: Resveratrol sustained-release targeting nanoparticles effectively inhibit in vivo ATC growth. Docetaxel/doxorubicin suppresses ATC xenografts but causes obvious side effects and secondary drug resistance that can be overcome by resveratrol.
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Affiliation(s)
- Le Xiong
- South China University of Technology School of Medicine, Guangzhou 510006, P.R. China
| | - Xiao-Min Lin
- South China University of Technology School of Medicine, Guangzhou 510006, P.R. China
| | - Jun-Hua Nie
- South China University of Technology School of Medicine, Guangzhou 510006, P.R. China
| | - Hai-Shan Ye
- South China University of Technology School of Medicine, Guangzhou 510006, P.R. China
| | - Jia Liu
- South China University of Technology School of Medicine, Guangzhou 510006, P.R. China
- Guangzhou First People's Hospital, South China University of Technology (SCUT) School of Medicine, Guangzhou 510180, China
- Liaoning Laboratory of Cancer Genomics, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
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