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Rafiyan M, Tootoonchi E, Golpour M, Davoodvandi A, Reiter RJ, Asemi R, Sharifi M, Rasooli Manesh SM, Asemi Z. Melatonin for gastric cancer treatment: where do we stand? NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1265-1282. [PMID: 39287677 DOI: 10.1007/s00210-024-03451-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/10/2024] [Indexed: 09/19/2024]
Abstract
Gastric cancer (GC) is the third leading reason of death in men and the fourth in women. Studies have documented an inhibitory function of melatonin on the proliferation, progression and invasion of GC cells. MicroRNAs (miRNAs) are small, non-coding RNAs that play an important function in regulation of biological processes and gene expression of the cells. Some studies reported that melatonin can suppress the progression of GC by regulating the exosomal miRNAs. Thus, melatonin represents a promising potential therapeutic agent for subjects with GC. Herein, we evaluate the existing data of both in vivo and in vitro studies to clarify the molecular processes involved in the therapeutic effects of melatonin in GC. The data emphasize the critical function of melatonin in several signaling ways by which it may inhibit cancer cell proliferation, decrease chemo-resistance, induce apoptosis as well as limit invasion, angiogenesis, and metastasis. This review provides a resource that identifies some of the mechanisms by which melatonin controls GC enlargement. In light of the findings, melatonin should be considered a novel and testable therapeutic mediator for GC treatment.
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Affiliation(s)
- Mahdi Rafiyan
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Elham Tootoonchi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mahdieh Golpour
- Student Research Committee, Mazandarn University of Medical Sciences, Sari, Mazandaran, Iran
| | - Amirhossein Davoodvandi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health. Long School of Medicine, San Antonio, TX, USA
| | - Reza Asemi
- Department of Internal Medicine, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehran Sharifi
- Department of Internal Medicine, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Dehghanzad M, Mohammadi M, Nejati M, Pouremamali F, Maroufi NF, Akbarzadeh M, Samadi N, Nouri M. The potential therapeutic effect of melatonin in oxaliplatin combination therapy against chemoresistant colorectal cancer cells. Mol Biol Rep 2024; 51:348. [PMID: 38401018 DOI: 10.1007/s11033-024-09316-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 02/02/2024] [Indexed: 02/26/2024]
Abstract
BACKGROUND Oxaliplatin is one of the main therapeutics in colorectal cancer (CRC) chemotherapy. However, in light of multidrug resistance (MDR) phenotype development, the efficacy of oxaliplatin has decreased. This study aimed to assess the potential therapeutic effect of melatonin in oxaliplatin combination therapy for drug-resistant colorectal cancer cells. METHODS AND RESULTS Initially, the oxaliplatin-resistant cell line was created of LS174T (LS174T/DR) by using the oxaliplatin IC50 concentration and resting cycles. MTT assays and flow cytometry were applied for assessing cell viability and apoptotic cells. The mRNA expression level of Bax, Bcl2, MT1, MT2, and ABCB1 as well as protein levels of ABCB1, Bcl2, BAX were measured by the qRT-PCR and western blot techniques respectively. P-gp activity was assessed by Rho123 staining. The IC50 concentration of oxaliplatin in resistant cells was increased from 500.7 ± 0.2 nM to 7119 ± 0.1 nM. Bcl2, MT1, MT2, and ABCB1 mRNA plus protein expression levels of Bcl2 and ABCB1 were significantly reduced in resistant cells, along with a marked increase in Bax mRNA and protein levels compared to parental cells. Rho 123 staining revealed a marked reduction in P-gp activities in the combination-treated group compared to the oxaliplatin-treated group. CONCLUSIONS The results of cytotoxicity assays, MTT, and flow cytometry revealed that the combination of melatonin and oxaliplatin exerts synergistic effects on induction of oxaliplatin's cytotoxicity in CRC. Our research suggests that combining the treatments of melatonin and oxaliplatin may be considered as a new approach to overcoming oxaliplatin resistance in CRC patients.
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Affiliation(s)
- Masoumeh Dehghanzad
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Gholgasht Ave, Tabriz, Iran
| | - Mohammad Mohammadi
- Department of Medical Laboratory Science, Faculty of Medicine, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
| | - Mohaddeseh Nejati
- Department of Biology, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Farhad Pouremamali
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Fathi Maroufi
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Gholgasht Ave, Tabriz, Iran
- Department of Human Genetics, McGill University, Montreal, Canada
- Victor Philip Dahdaleh Institute of Genomic Medicine at McGill University, Montreal, Canada
| | - Maryam Akbarzadeh
- Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Naser Samadi
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Gholgasht Ave, Tabriz, Iran
| | - Mohammad Nouri
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Gholgasht Ave, Tabriz, Iran.
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Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol 2023; 97:2499-2574. [PMID: 37597078 PMCID: PMC10475008 DOI: 10.1007/s00204-023-03562-9] [Citation(s) in RCA: 631] [Impact Index Per Article: 315.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 07/24/2023] [Indexed: 08/21/2023]
Abstract
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Renata Raptova
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Saleh H Alwasel
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia.
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Dincer B, Yildiztekin G, Cinar I. Unlocking Synergistic Potential: Agomelatine Enhances the Chemotherapeutic Effect of Paclitaxel in Breast Cancer Cell Through MT1 Melatonin Receptors and ER-alpha Axis. Chem Biodivers 2023; 20:e202301093. [PMID: 37690997 DOI: 10.1002/cbdv.202301093] [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: 07/24/2023] [Revised: 09/07/2023] [Accepted: 09/10/2023] [Indexed: 09/12/2023]
Abstract
This study investigates the potential of agomelatine (AGO), a synthetic melatoninergic drug, in combination with paclitaxel (PTX) for the treatment of breast cancer. The effects of AGO, PTX and melatonin (MTN) on breast cancer cell viability were investigated, focusing on the role of MT1 receptors. Cell viability and gene expression were analyzed in MCF-7 and MDA-MB-231 breast cancer cell experiments. The results show that AGO has cytotoxic effects on breast cancer cells similar to MTN. Combining AGO and MTN with PTX showed synergistic effects in MCF-7 cells. The study also reveals differences in the molecular mechanisms of breast cancer between estrogen-positive MCF-7 cells and estrogen-negative MDA-MB-231 cells. Combination with AGO and PTX affects apoptosis-associated proteins in both cell types. The findings suggest that AGO, combined with PTX, may be a promising adjuvant therapy for breast cancer and highlight the importance of MTN receptors in its mechanism of action.
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Affiliation(s)
- Busra Dincer
- Department of Pharmacology, Faculty of Pharmacy, Ondokuz Mayıs University, Samsun, 55100, Turkey
| | - Gizem Yildiztekin
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erzincan Binali Yildirim University, Erzincan, 24100, Turkey
| | - Irfan Cinar
- Department of Pharmacology, Faculty of Medicine, Kastamonu University, Kastamonu, 37150, Turkey
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Tran CTD, Paragomi P, Tran MT, Nguyen MVT, Tuong TTV, Tran QH, Le LC, Pham HTT, Ha HTT, Bui NC, Vu HH, Ta PQ, Shrubsole MJ, Cai Q, Ye F, Le SH, Van Vu K, Tran HTT, Van Tran T, Boffetta P, Shu XO, Luu HN. Association between Sleep Duration and Colorectal Adenomas: Findings from a Case-Control Study in Vietnam. Cancer Epidemiol Biomarkers Prev 2023; 32:1160-1168. [PMID: 37314746 PMCID: PMC10527343 DOI: 10.1158/1055-9965.epi-23-0056] [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: 01/17/2023] [Revised: 04/12/2023] [Accepted: 06/12/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Colorectal cancer is one of the leading cancers worldwide and in Vietnam. Adenomas are important precursors of colorectal cancer. Study on the association between sleep duration and development of colorectal adenoma (CRA) is limited, particularly among Vietnamese population. METHODS We conducted an individually matched case-control study of 870 CRA cases and 870 controls in a large-scale colorectal screening program involving 103,542 individuals ages ≥40 years old in Hanoi, Vietnam. Sleep duration was categorized in three groups: short: ≤6 hours/day, normal: 7 to 8 hours/day, and long: >8 hours/day. Conditional logistic regression was used to evaluate the association between sleep duration and adenomas risk after controlling for potential confounders. RESULTS Overall, short-sleep duration was associated with increased risk of having CRA compared with normal duration [OR, 1.48; 95% confidence interval (CI), 1.12-1.97]. This pattern was present in both females (OR, 1.58; 95% CI, 1.14-2.18) and males (OR, 1.45; 95% CI, 1.08-1.93), with advanced adenomas (OR, 1.61; 95% CI, 1.09-2.38) and non-advanced adenomas (OR, 1.66; 95% CI, 1.19-2.32). Furthermore, the association between CRA development and short-sleep duration was more apparent among females who were nondrinker, nonobese, physically active, with proximal or both sided adenomas and with cardiometabolic disorder. Among males, the short-sleep duration was associated with CRA risk among never-smoking, cardiometabolic disorders, and obese. CONCLUSIONS Short-sleep duration was associated with increased prevalence of both advanced and non-advanced CRAs among Vietnamese population. IMPACT Findings from this study showed that maintaining an adequate sleep duration may have an important implication for colorectal adenoma prevention and control.
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Affiliation(s)
- Chi Thi-Du Tran
- Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam
- College of Health Sciences, VinUniversity (VinUni), Hanoi, Vietnam
- Center of Applied Sciences, Regenerative Medicine and Advanced Technologies, Vinmec Healthcare System, Hanoi, Vietnam
| | - Pedram Paragomi
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC), 5150 Centre Avenue, Suite 4C, Pittsburgh, PA, 15232
| | - Mo Thi Tran
- Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam
| | - Mai Vu-Tuyet Nguyen
- Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam
| | - Thuy Thi-Van Tuong
- Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quang Hong Tran
- Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam
| | - Linh Cu Le
- College of Health Sciences, VinUniversity (VinUni), Hanoi, Vietnam
| | - Huong Thi-Thu Pham
- Department of Gastroenterology, Vinmec International Hospital at Times city, Vinmec Healthcare system, Hanoi, Vietnam
| | - Hien Thi-Thu Ha
- Department of Histopathology, Vinmec International Hospital at Times city, Vinmec Healthcare system, Hanoi, Vietnam
| | - Nam Chi Bui
- Department of Gastroenterology, Vinmec International Hospital at Times city, Vinmec Healthcare system, Hanoi, Vietnam
| | - Hien Huy Vu
- Department of Gastroenterology, Vinmec International Hospital at Times city, Vinmec Healthcare system, Hanoi, Vietnam
| | - Phuong Que Ta
- Department of Gastroenterology, Vinmec International Hospital at Times city, Vinmec Healthcare system, Hanoi, Vietnam
| | - Martha J. Shrubsole
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Fei Ye
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Song Huu Le
- Center of Molecular and Genetic Research, 108 Hospital, Hanoi, Vietnam
| | - Khien Van Vu
- Department of Gastroenterology, 108 Hospital, Hanoi, Vietnam
| | - Huong Thi-Thanh Tran
- Vietnam National Cancer Institute, Vietnam National Cancer Hospital, Hanoi, Vietnam
- Department of Ethics and Medical Psychology, Hanoi Medical University, Hanoi, Vietnam
| | - Thuan Van Tran
- Vietnam National Cancer Institute, Vietnam National Cancer Hospital, Hanoi, Vietnam
- Vietnam Ministry of Health, Hanoi, Vietnam
| | - Paolo Boffetta
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Xiao-Ou Shu
- Department of Histopathology, Vinmec International Hospital at Times city, Vinmec Healthcare system, Hanoi, Vietnam
| | - Hung N. Luu
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC), 5150 Centre Avenue, Suite 4C, Pittsburgh, PA, 15232
- Department of Epidemiology, School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA 15261
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Wang K, Cai R, Fei S, Chen X, Feng S, Zhang L, Liu H, Zhang Z, Song J, Zhou R. Melatonin enhances anti-tumor immunity by targeting macrophages PD-L1 via exosomes derived from gastric cancer cells. Mol Cell Endocrinol 2023; 568-569:111917. [PMID: 37028587 DOI: 10.1016/j.mce.2023.111917] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/09/2023]
Abstract
Melatonin (MLT) is a hormone with potential anti-tumor properties, but the molecular mechanisms remain unclear. The present study aimed to explore the effect of MLT on exosomes derived from gastric cancer cells, with the goal of gaining insight into its anti-tumor activity. Results from in vitro experiments showed that MLT was able to enhance the anti-tumor activity of macrophages that had been suppressed by exosomes from gastric cancer cells. This effect was achieved through regulation of the levels of PD-L1 in macrophages via modulation of the associated microRNAs in the cancer-derived exosomes. Furthermore, MLT treatment increased the secretion of TNF-α and CXCL10 by the macrophages. Besides, MLT treatment of gastric cancer cells led to the production of exosomes that promoted the recruitment of CD8+ T cells to the tumor site, resulting in inhibition of tumor growth. Collectively, these results provide evidence for the modulation of the tumor immune microenvironment by MLT through regulation of exosomes derived from gastric cancer cells, suggesting a potential role for MLT in novel anti-tumor immunotherapies.
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Affiliation(s)
- Kaifang Wang
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China; School of Dentistry, Shenzhen University Medical School, Shenzhen, China; Department of Biology, Faculty of Science, Hong Kong Baptist University, Hongkong, China.
| | - Rong Cai
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Shuting Fei
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Xuzheng Chen
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Sisi Feng
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Lulu Zhang
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Hui Liu
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zhiguang Zhang
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Jun Song
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
| | - Ruixiang Zhou
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
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Li J, Cao D, Huang Y, Chen Z, Wang R, Dong Q, Wei Q, Liu L. Sleep duration and health outcomes: an umbrella review. Sleep Breath 2022; 26:1479-1501. [PMID: 34435311 DOI: 10.1007/s11325-021-02458-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/18/2021] [Accepted: 07/28/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE To collect existing evidence on the relationship between sleep duration and health outcomes. METHODS A thorough search was conducted in PubMed, Web of Science, Embase, and the Cochrane Database of Systematic Reviews from inception to January, 2021. Meta-analyses of observational and interventional studies were eligible if they examined the associations between sleep duration and human health. RESULTS In total, this umbrella review identified 69 meta-analyses with 11 outcomes for cancers and 30 outcomes for non-cancer conditions. Inappropriate sleep durations may significantly elevate the risk for cardiovascular disease (CVD), cognitive decline, coronary heart disease (CHD), depression, falls, frailty, lung cancer, metabolic syndrome (MS), and stroke. Dose-response analysis revealed that a 1-h reduction per 24 hours is associated with an increased risk by 3-11% of all-cause mortality, CHD, osteoporosis, stroke, and T2DM among short sleepers. Conversely, a 1-h increment in long sleepers is associated with a 7-17% higher risk of stroke mortality, CHD, stroke, and T2DM in adults. CONCLUSION Inappropriate sleep duration is a risk factor for developing non-cancer conditions. Decreasing and increasing sleep hours towards extreme sleep durations are associated with poor health outcomes.
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Affiliation(s)
- Jin Li
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Dehong Cao
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yin Huang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Zeyu Chen
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Ruyi Wang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qiang Dong
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qiang Wei
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Liangren Liu
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
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Titova OE, Michaëlsson K, Vithayathil M, Mason AM, Kar S, Burgess S, Larsson SC. Sleep duration and risk of overall and 22 site-specific cancers: A Mendelian randomization study. Int J Cancer 2021; 148:914-920. [PMID: 32895918 PMCID: PMC7821333 DOI: 10.1002/ijc.33286] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 12/11/2022]
Abstract
Studies of sleep duration in relation to the risk of site-specific cancers other than breast cancer are scarce. Furthermore, the available results are inconclusive and the causality remains unclear. We aimed to investigate the potential causal associations of sleep duration with overall and site-specific cancers using the Mendelian randomization (MR) design. Single-nucleotide polymorphisms associated with the sleep traits identified from a genome-wide association study were used as instrumental variables to estimate the association with overall cancer and 22 site-specific cancers among 367 586 UK Biobank participants. A replication analysis was performed using data from the FinnGen consortium (up to 121 579 individuals). There was suggestive evidence that genetic liability to short-sleep duration was associated with higher odds of cancers of the stomach (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.15-4.30; P = .018), pancreas (OR, 2.18; 95% CI, 1.32-3.62; P = .002) and colorectum (OR, 1.48; 95% CI, 1.12-1.95; P = .006), but with lower odds of multiple myeloma (OR, 0.47; 95% CI, 0.22-0.99; P = .047). Suggestive evidence of association of genetic liability to long-sleep duration with lower odds of pancreatic cancer (OR, 0.44; 95% CI, 0.25-0.79; P = .005) and kidney cancer (OR, 0.44; 95% CI, 0.21-0.90; P = .025) was observed. However, none of these associations passed the multiple comparison threshold and two-sample MR analysis using FinnGen data did not confirm these findings. In conclusion, this MR study does not provide strong evidence to support causal associations of sleep duration with risk of overall and site-specific cancers. Further MR studies are required.
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Affiliation(s)
- Olga E. Titova
- Unit of Medical Epidemiology, Department of Surgical SciencesUppsala UniversityUppsalaSweden
| | - Karl Michaëlsson
- Unit of Medical Epidemiology, Department of Surgical SciencesUppsala UniversityUppsalaSweden
| | | | - Amy M. Mason
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
- National Institute for Health Research Cambridge Biomedical Research CentreUniversity of Cambridge and Cambridge University HospitalsCambridgeUK
| | - Siddhartha Kar
- MRC Integrative Epidemiology Unit, Bristol Medical SchoolUniversity of BristolBristolUK
| | - Stephen Burgess
- Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
- MRC Biostatistics UnitUniversity of CambridgeCambridgeUK
| | - Susanna C. Larsson
- Unit of Medical Epidemiology, Department of Surgical SciencesUppsala UniversityUppsalaSweden
- Unit of Cardiovascular and Nutritional EpidemiologyInstitute of Environmental Medicine, Karolinska InstitutetStockholmSweden
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Pourhanifeh MH, Mehrzadi S, Kamali M, Hosseinzadeh A. Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways. Eur J Pharmacol 2020; 886:173471. [PMID: 32877658 DOI: 10.1016/j.ejphar.2020.173471] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 02/06/2023]
Abstract
Gastrointestinal (GI) cancers, leading causes of cancer-related deaths, have been serious challenging human diseases up to now. Because of high rates of mortality, late-stage diagnosis, metastasis to distant locations, and low effectiveness and adverse events of routine standard therapies, the quality of life and survival time are low in patients with GI cancers. Hence, many efforts need to be done to explore and find novel efficient treatments. Beneficial effects of melatonin have been reported in a wide variety of human diseases. Melatonin has antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. Various studies have showed the regulatory effects of melatonin on apoptotsis, autophagy and angiogenesis; these properties result in the inhibition of invasion, migration, and proliferation of GI cancer cells in vivo and in vitro. Together, this review suggests that melatonin in combination with anticancer agents may improve the efficacy of routine medicine and survival rate of patients with cancer.
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Affiliation(s)
- Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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10
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Bjørklund G, Rajib SA, Saffoon N, Pen JJ, Chirumbolo S. Insights on Melatonin as an Active Pharmacological Molecule in Cancer Prevention: What's New? Curr Med Chem 2019; 26:6304-6320. [PMID: 29714136 DOI: 10.2174/0929867325666180501094850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/10/2018] [Accepted: 04/18/2018] [Indexed: 12/12/2022]
Abstract
Along with playing an important role in circadian rhythm, melatonin is thought to play a significant role in preventing cells from damage, as well as in the inhibition of growth and in triggering apoptosis in malignant cells. Its relationship with circadian rhythms, energetic homeostasis, diet, and metabolism, is fundamental to achieve a better comprehension of how melatonin has been considered a chemopreventive molecule, though very few papers dealing with this issue. In this article, we tried to review the most recent evidence regarding the protective as well as the antitumoral mechanisms of melatonin, as related to diet and metabolic balance. From different studies, it was evident that an intracellular antioxidant defense mechanism is activated by upregulating an antioxidant gene battery in the presence of high-dose melatonin in malignant cells. Like other broad-spectrum antioxidant molecules, melatonin plays a vital role in killing tumor cells, preventing metastasis, and simultaneously keeping normal cells protected from oxidative stress and other types of tissue damage.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
| | | | - Nadia Saffoon
- Department of Pharmacy and Forensic Science, Faculty of Life Science and Medicine, King's College London, London, United Kingdom
| | - Joeri J Pen
- Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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11
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Wang Q, Sun Z, Du L, Xu C, Wang Y, Yang B, He N, Wang J, Ji K, Liu Y, Liu Q. Melatonin Sensitizes Human Colorectal Cancer Cells to γ-ray Ionizing Radiation In Vitro and In Vivo. Int J Mol Sci 2018; 19:ijms19123974. [PMID: 30544713 PMCID: PMC6320774 DOI: 10.3390/ijms19123974] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/04/2018] [Accepted: 12/07/2018] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is the most commonly reported gastrointestinal malignancy, with a recent, rapid increase of the annual incidence all over the world. Enhancing the radiosensitivity of cancer cells while preserving the health of normal cells is one of the most important tasks in clinical radiobiology. However, resistance to radiotherapy for colorectal cancer greatly decreases the therapeutic outcome. Melatonin (N-acetyl-5-methoxytryptamine), a natural secretory product that the pineal gland in the brain normally produces, has been reported to have anticancer properties. In the study, we investigated the combination of melatonin with radiotherapy as a treatment for colorectal cancer. We firstly explored the anti-tumor activity of melatonin combined with ionizing radiation (IR) against colorectal carcinoma in vitro. It was found that melatonin effectively inhibited human colorectal carcinoma cell line HCT 116 cellular proliferation, colony formation rate and cell migration counts following IR. Increasing the radiosensitivity of colorectal cancer cells by melatonin treatment was found to be associated with cell cycle arrest in the G2/M phase, downregulation of proteins involved in DNA double-strand break repair and activation of the caspase-dependent apoptotic pathway. Moreover, we also investigated the combined effect of IR and melatonin on colorectal tumor in vivo. Results from a tumor xenograft showed that melatonin plus IR treatment significantly suppressed tumor cell growth compared with melatonin or IR alone, resulting in a much higher tumor inhibition rate for the combined treatment. The data suggested that melatonin combined with IR could improve the radiosensitivity of colorectal cancer and thus enhance the therapeutic effect of the patients, implying melatonin could function as a potential sensitizer in tumor radiotherapy.
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Affiliation(s)
- Qin Wang
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Zhijuan Sun
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Liqing Du
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Chang Xu
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Yan Wang
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Bing Yang
- Department of Cellular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
| | - Ningning He
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Jinhan Wang
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Kaihua Ji
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Yang Liu
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
| | - Qiang Liu
- Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
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12
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Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Melatonin for the prevention and treatment of cancer. Oncotarget 2018; 8:39896-39921. [PMID: 28415828 PMCID: PMC5503661 DOI: 10.18632/oncotarget.16379] [Citation(s) in RCA: 247] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 03/09/2017] [Indexed: 12/17/2022] Open
Abstract
The epidemiological studies have indicated a possible oncostatic property of melatonin on different types of tumors. Besides, experimental studies have documented that melatonin could exert growth inhibition on some human tumor cells in vitro and in animal models. The underlying mechanisms include antioxidant activity, modulation of melatonin receptors MT1 and MT2, stimulation of apoptosis, regulation of pro-survival signaling and tumor metabolism, inhibition on angiogenesis, metastasis, and induction of epigenetic alteration. Melatonin could also be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. Melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as breast cancer, prostate cancer, gastric cancer and colorectal cancer. This review summarized the anticancer efficacy of melatonin, based on the results of epidemiological,experimental and clinical studies, and special attention was paid to the mechanisms of action.
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Affiliation(s)
- Ya Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yue Zhou
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Xiao Meng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Jiao-Jiao Zhang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Dong-Ping Xu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China.,South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-Sen University, Guangzhou, China
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13
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Asghari MH, Moloudizargari M, Ghobadi E, Fallah M, Abdollahi M. Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer. Life Sci 2017; 185:38-45. [DOI: 10.1016/j.lfs.2017.07.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 07/14/2017] [Accepted: 07/20/2017] [Indexed: 12/13/2022]
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14
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Li W, Wang Z, Chen Y, Wang K, Lu T, Ying F, Fan M, Li Z, Wu J. Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells. Oncol Lett 2017; 13:2737-2744. [PMID: 28454460 DOI: 10.3892/ol.2017.5785] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 12/09/2016] [Indexed: 12/13/2022] Open
Abstract
Melatonin, which is synthesized by the pineal gland and released into the blood, exhibits antitumor properties. However, the mechanisms underlying these effects, particularly in stomach cancer, remain unknown. In the present study, the effect of melatonin on the nuclear factor (NF)-κB signaling pathway and the mitogen-activated protein kinase signaling pathway, involving p38 and c-Jun-N-terminal kinase (JNK), were investigated in SGC7901 gastric cancer cells. In addition, the effect of melatonin on the survival, migration and apoptosis of these cells was investigated in vitro in order to evaluate the use of melatonin for the treatment of gastric cancer. The results of the present study revealed that melatonin decreased the viability and migration of SGC7901 cells. Furthermore, melatonin induced apoptosis. Melatonin was identified to elevate the expression levels of phosphorylated (p)-p38 and p-JNK protein, and decrease the expression level of nucleic p-p65. These results suggest that the protein levels of p65, p38 and JNK are associated with the survival of SGC7901 cells following treatment with melatonin. The optimal concentration of melatonin was demonstrated to be 2 mM, which significantly induced apoptosis following a 24 h treatment period. These findings suggest that conflicting growth signals in cells may inhibit the efficacy of melatonin in the treatment of gastric cancer. Therefore, adjunct therapy would be required to improve the efficacy of melatonin in the treatment of cancer.
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Affiliation(s)
- Weimin Li
- Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China.,Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhonglue Wang
- Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Yina Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Kaijing Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Ting Lu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Gastroenterology, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang 315000, P.R. China
| | - Fei Ying
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Gastroenterology, Xianju People's Hospital, Taizhou, Zhejiang 317300, P.R. China
| | - Mengdi Fan
- Department of Endocrinology, Zhejiang University International Hospital, Hangzhou, Zhejiang 310000, P.R. China
| | - Zhiyin Li
- Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Jiansheng Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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15
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Li W, Wu J, Li Z, Zhou Z, Zheng C, Lin L, Tan B, Huang M, Fan M. Melatonin induces cell apoptosis in Mia PaCa-2 cells via the suppression of nuclear factor-κB and activation of ERK and JNK: A novel therapeutic implication for pancreatic cancer. Oncol Rep 2016; 36:2861-2867. [DOI: 10.3892/or.2016.5100] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 06/30/2016] [Indexed: 11/05/2022] Open
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16
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Wang RX, Liu H, Xu L, Zhang H, Zhou RX. Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo. Oncol Lett 2016; 12:897-903. [PMID: 27446366 PMCID: PMC4950661 DOI: 10.3892/ol.2016.4729] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Accepted: 04/01/2016] [Indexed: 12/27/2022] Open
Abstract
An adequate supply of oxygen and nutrients, derived from the formation of novel blood vessels, is critical for the growth and expansion of tumor cells. It has been demonstrated that melatonin (MLT) exhibits marked in vitro and in vivo oncostatic activities. The primary purpose of the present study was to evaluate the in vitro and in vivo antitumor activity of MLT on the growth and angiogenesis of gastric cancer cells, and explore the underlying molecular mechanisms. The present results revealed that MLT inhibited the growth of gastric cancer SGC-7901 cells in a dose- and time-dependent manner. In addition, the present study demonstrated that low concentrations (0.01, 0.1 and 1 mM) of MLT had no clear effect on vascular endothelial growth factor (VEGF) secretion, whereas a high concentration (3 mM) of MLT suppressed VEGF secretion in SGC-7901 cells. Notably, administration of MLT caused suppression of gastric cancer growth and blockade of tumor angiogenesis in tumor-bearing nude mice. Furthermore, MLT treatment reduced the expression of the MLT nuclear receptor RZR/RORγ, SUMO-specific protease 1, hypoxia-inducible factor-1α and VEGF at transcriptional and translational levels within gastric cancer cells during tumorigenesis. In conclusion, MLT nuclear receptor RZR/RORγ may be of great importance in the MLT mediated anti-angiogenesis and growth-inhibitory effect in gastric cancer cells. Since RZR/RORγ is overexpressed in multiple human cancers, MLT may be a promising agent for the treatment of cancers.
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Affiliation(s)
- Ri-Xiong Wang
- Department of Chemotherapy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
| | - Hui Liu
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Neurobiology Research Center, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
| | - Li Xu
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Neurobiology Research Center, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
| | - Hui Zhang
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Neurobiology Research Center, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
| | - Rui-Xiang Zhou
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- Neurobiology Research Center, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
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17
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Zhou B, Sun Q, Kong DX. Predicting cancer-relevant proteins using an improved molecular similarity ensemble approach. Oncotarget 2016; 7:32394-407. [PMID: 27083051 PMCID: PMC5078021 DOI: 10.18632/oncotarget.8716] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 03/28/2016] [Indexed: 12/15/2022] Open
Abstract
In this study, we proposed an improved algorithm for identifying proteins relevant to cancer. The algorithm was named two-layer molecular similarity ensemble approach (TL-SEA). We applied TL-SEA to analyzing the correlation between anticancer compounds (against cell lines K562, MCF7 and A549) and active compounds against separate target proteins listed in BindingDB. Several associations between cancer types and related proteins were revealed using this chemoinformatics approach. An analysis of the literature showed that 26 of 35 predicted proteins were correlated with cancer cell proliferation, apoptosis or differentiation. Additionally, interactions between proteins in BindingDB and anticancer chemicals were also predicted. We discuss the roles of the most important predicted proteins in cancer biology and conclude that TL-SEA could be a useful tool for inferring novel proteins involved in cancer and revealing underlying molecular mechanisms.
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Affiliation(s)
- Bin Zhou
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Qi Sun
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - De-Xin Kong
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
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18
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Wang RX, Liu H, Xu L, Zhang H, Zhou RX. Involvement of nuclear receptor RZR/RORγ in melatonin-induced HIF-1α inactivation in SGC-7901 human gastric cancer cells. Oncol Rep 2015; 34:2541-6. [PMID: 26330273 DOI: 10.3892/or.2015.4238] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 08/04/2015] [Indexed: 11/06/2022] Open
Abstract
The melatonin nuclear receptor is an orphan member of the nuclear receptor superfamily RZR/ROR, which consists of three subtypes (α, β and γ), suggesting that immunomodulatory and antitumor effects through the intracellular action of melatonin depend on nuclear signaling. In the present study, the biological mechanisms of melatonin were elucidated in association with the RZR/RORγ pathway in SGC-7901 human gastric cancer cells under hypoxia. Melatonin suppressed the activity of RZR/RORγ and SUMO-specific protease 1 (SENP1) signaling pathway, which is essential for stabilization of hypoxia‑inducible factor-1α (HIF‑1α) during hypoxia. Furthermore, melatonin inhibited the stability of HIF-1α in a time- and conce-ntration-dependent manner in SGC-7901 human gastric cancer cells during hypoxia. Consistently, siRNA-RZR/RORγ effectively blocked the expression of SENP1, HIF-1α and vascular endothelial growth factor (VEGF) production in SGC-7901 cells under hypoxia, suggesting the role of nuclear receptor RZR/RORγ in melatonin-inhibited HIF-1α and VEGF accumulation. Moreover, siRNA RZR/RORγ obviously antagonized to inhibit the action of the gastric cancer cell proliferation by melatonin. Our findings suggest that melatonin suppresses HIF-1α accumulation and VEGF generation via inhibition of melatonin nuclear receptor RZR/RORγ in SGC-7901 cells under hypoxia.
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Affiliation(s)
- Ri-Xiong Wang
- The Chemotherapy Department of The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Hui Liu
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Li Xu
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Hui Zhang
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Rui-Xiang Zhou
- Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China
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Xin Z, Jiang S, Jiang P, Yan X, Fan C, Di S, Wu G, Yang Y, Reiter RJ, Ji G. Melatonin as a treatment for gastrointestinal cancer: a review. J Pineal Res 2015; 58:375-87. [PMID: 25752643 DOI: 10.1111/jpi.12227] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 03/04/2015] [Indexed: 02/06/2023]
Abstract
Gastrointestinal cancer is a disease that affects the population worldwide with high morbidity and mortality. Melatonin, an endogenously produced molecule, may provide a defense against a variety of cancer types. In particular, the ability of melatonin to inhibit gastrointestinal cancer is substantial. In this review, we first clarify the relationship between the disruption of the melatonin rhythm and gastrointestinal cancer (based on epidemiologic surveys and animal and human studies) and summarize the preventive effect of melatonin on carcinogenesis. Thereafter, the mechanisms through which melatonin exerts its anti-gastrointestinal cancer actions are explained, including inhibition of proliferation, invasion, metastasis, and angiogenesis, and promotion of apoptosis and cancer immunity. Moreover, we discuss the drug synergy effects and the role of melatonin receptors involved in the growth-inhibitory effects on gastrointestinal cancer. Taken together, the information compiled here serves as a comprehensive reference for the anti-gastrointestinal cancer actions of melatonin that have been identified to date and will hopefully aid in the design of further experimental and clinical studies and increase the awareness of melatonin as a therapeutic agent in cancers of the gastrointestinal tract.
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Affiliation(s)
- Zhenlong Xin
- State Key Laboratory of Cancer Biology, Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China
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Verma S, Kesh K, Ganguly N, Jana S, Swarnakar S. Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants. World J Biol Chem 2014; 5:355-376. [PMID: 25225603 PMCID: PMC4160529 DOI: 10.4331/wjbc.v5.i3.355] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 05/07/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases (MMPs). Degradation of extracellular matrix (ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metalloproteinase (TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK (reversion including cysteine-rich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2, -9 and -14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species (ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows.
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21
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Bizzarri M, Proietti S, Cucina A, Reiter RJ. Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opin Ther Targets 2013; 17:1483-96. [DOI: 10.1517/14728222.2013.834890] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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