Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis |
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| Institution: | 1. Department of Pharmacognosy and Phytochemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad 380054, Gujarat, India;2. Registered Ph.D. student at Department of Life science, School of Science, Gujarat University, Ahmedabad, Gujarat, India;1. Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China;2. Department of Clinical Nutrition, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;1. Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan ROC;2. Department of Medicine Chest, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan ROC;3. Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, Taipei 11221, Taiwan ROC;4. Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan ROC;5. Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC;6. Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan ROC;7. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC;8. Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC;1. Graduate Institute of Health Industry Technology and Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan 333, Taiwan;2. Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 333, Taiwan;3. Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan 333, Taiwan;4. Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan |
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| Abstract: | BackgroundSulforaphane (SFN) is a naturally occurring organosulfur compound found in cruciferous vegetables such as broccoli, brussels sprouts and cabbage. SFN is known for its multiple therapeutic properties, such as HDAC inhibitory, chemo preventive and anti-cancer effects. Cisplatin (CIS) has limited effect against metastatic triple-negative breast cancer (TNBC). Additionally, CIS impose severe side effects to normal cells, and later TNBC cells develops resistance. Studies suggest that the overexpression of sirtuins (SIRTs) promotes CIS resistance and metastasis by activating epithelial-to-mesenchymal transition (EMT) pathway in TNBC.PurposeIn view of the above information, we investigated the therapeutic efficacy of SFN, in combination with CIS against TNBC metastasis and CIS resistance.MethodsThe anti-cancerous effect of SFN-CIS combination on human TNBC cell lines was demonstrated by utilizing MTT assay and, apoptosis and cell cycle assay followed by FACS analysis. The synergistic effect of SFN-CIS combination on the experimental metastasis was demonstrated by utilizing migration, invasion, chemotaxis, mammosphere and colony formation assay on human TNBC MDA-MB-231 and MDA-MB-468 cells. The role of SIRTs-mediated EMT signaling axis in the metastasis and chemoresistance was investigated by western blotting technique as well as sirtuin activity tests. This was further validated by using Chromatin immunoprecipitation (ChIP) analysis.ResultsWe found that SFN-CIS combination synergistically inhibits cellular growth of MDA-MB-231 and MDA-MB-468 cells. More importantly, SFN was found to protect normal kidney cells from CIS-induced toxicity. Further, SFN-CIS combination was found to synergistically inhibit metastatic-events via significantly altering EMT markers which was further associated with the suppression of SIRTs functions in TNBC cells. ChIP analysis validated that SFN-CIS combination suppresses EMT mechanism through altered chromatin modifications at E-cadherin promoter resulting in its re-expression.ConclusionThe results of the current study suggests that CIS when supplemented with SFN, inhibits metastasis and stemness potential of TNBC cells by down regulating SIRTs-mediated EMT cascade. Overall this study affirms that, this novel combination could be a promising strategy against SIRT-mediated TNBC metastasis and CIS-resistance. |
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