title: Cytotoxic activity of soy phytoestrogen coumestrol against human breast cancer MCF-7 cells: Insights into the molecular mechanism.
abstract: Coumestrol is a phytoestrogen present in soybean products and recognized as potential cancer therapeutic agent against breast cancer. However, the clear molecular mechanism of anticancer-activity of coumestrol in breast carcinoma has not been reported. It is well established that copper levels are elevated in different malignancies. Therefore, the objective of this study was to investigate the copper-dependent cytotoxic action of coumestrol in human breast cancer MCF-7 cells. Results showed that coumestrol inhibited proliferation and induced apoptosis in MCF-7 cells, which was prevented by copper chelator neocuproine and ROS scavengers. Coumestrol treatment induced ROS generation coupled to DNA fragmentation, up-regulation of p53/p21, cell cycle arrest at G1/S phase, mitochondrial membrane depolarization and caspases 9/3 activation. All these effects were suppressed by ROS scavengers and neocuproine. These results suggest that coumestrol targets elevated copper for redox cycling to generate ROS leading to DNA fragmentation. DNA damage leads to p53 up-regulation which directs the cell cycle arrest at G1/S phase and promotes caspase-dependent apoptosis of MCF-7 cells. In conclusion, copper targeted ROS-mediated p53-dependent mechanism better explains the cytotoxic action of coumestrol in MCF-7 cells. Thus, targeting elevated copper levels might be a potential therapeutic strategy for selective cytotoxic action against malignant cells.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India.
authors.forename: Atif
authors.initials: A
authors.lastname: Zafar
authors.affiliation: Department of Dermatology and Venereology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
authors.forename: Swarnendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India. Electronic address: imrananaseem2009@gmail.com.
authors.forename: Imrana
authors.initials: I
authors.lastname: Naseem
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003375:Coumestrol / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D048789:Phytoestrogens / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013025:Glycine max / Q000737:chemistry*
chemical_list: D048789:Phytoestrogens; D017382:Reactive Oxygen Species; D003375:Coumestrol
keywords: Apoptosis; Breast cancer; Copper; Coumestrol; DNA damage; ROS