Deciphering the molecular mechanism underlying anticancer activity of coumestrol in triple-negative breast cancer cells

Zafar, A. and Singh, S. and Satija, Y.K. and Saluja, D. and Naseem, I. (2018) Deciphering the molecular mechanism underlying anticancer activity of coumestrol in triple-negative breast cancer cells. Toxicology in Vitro, 46. pp. 19-28. ISSN 8872333

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Triple-negative breast cancer (TNBC) represents the highly aggressive subgroup of breast cancers with poor prognosis due to absence of estrogen receptor (ER). Therefore, alternative targeted therapies are required against ER-negative breast cancers. Coumestrol, a phytoestrogen inhibits cell growth of ER-negative breast cancer MDA-MB-231 cells; the exact mechanism has not yet been reported. Unlike normal cells, cancer cells contain elevated copper which play an integral role in angiogenesis. The current focus of the work was to identify any possible role of copper in coumestrol cytotoxic action against breast cancer MDA-MB-231 cells. Results demonstrated that coumestrol inhibited cell viability, induced ROS generation, DNA damage, G1/S cell cycle arrest, up-regulation of Bax and apoptosis induction via caspase-dependent mitochondrial mediated pathway in MDA-MB-231 cells. Further, addition of copper chelator, neocuproine and ROS scavenger, N-acetyl cysteine were ineffective in abrogating coumestrol-mediated apoptosis. This suggests non-involvement of copper and ROS in coumestrol-induced apoptosis. To account for coumestrol-mediated up-regulation of Bax and apoptosis induction, direct binding potential between coumestrol and Bax/Bcl-2 was studied using in silico molecular docking studies. We propose that coumestrol directly enters cells and combines with Bax/Bcl-2 to alter their structures, thereby causing Bax binding to the outer mitochondrial membrane and Bcl-2 release from the mitochondria to initiate apoptosis. Thus, non-copper targeted ROS independent DNA damage is the central mechanism of coumestrol in ER-negative MDA-MB-231 cells. These findings will be useful in better understanding of anticancer mechanisms of coumestrol and establishing it as a lead molecule for TNBC treatment.

Item Type: Article
Uncontrolled Keywords: Apoptosis; Coumestrol; DNA damage; ROS; Triple negative breast cancer
Divisions: Faculties > Faculty of Life Sciences > Department of Biochemistry
Depositing User: AMU Library
Date Deposited: 20 Jan 2018 05:12
Last Modified: 20 Jan 2018 05:12

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