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

Area of Science:

• * Oncology
• * Molecular Biology
• * Pharmacology

Background:

• * Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors (ER), necessitating alternative targeted therapies.
• * Coumestrol, a phytoestrogen, shows potential in inhibiting ER-negative breast cancer cell growth, but its mechanism remains unclear.
• * Elevated copper levels in cancer cells and its role in angiogenesis warrant investigation into its interaction with therapeutic agents.

Purpose of the Study:

• * To elucidate the mechanism of coumestrol's cytotoxic action against ER-negative breast cancer MDA-MB-231 cells.
• * To investigate the potential role of copper and reactive oxygen species (ROS) in coumestrol-induced apoptosis.
• * To explore the direct interaction between coumestrol and apoptosis-regulating proteins (Bax/Bcl-2).

Main Methods:

• * Cell viability assays and assessment of ROS generation, DNA damage, and cell cycle progression.
• * Induction of apoptosis via caspase-dependent mitochondrial pathways.
• * In silico molecular docking studies to evaluate coumestrol binding to Bax and Bcl-2 proteins.

Main Results:

• * Coumestrol inhibited MDA-MB-231 cell viability, induced DNA damage, G1/S cell cycle arrest, and apoptosis.
• * Copper chelators and ROS scavengers did not affect coumestrol-mediated apoptosis, indicating non-involvement of copper and ROS.
• * Molecular docking suggested direct binding of coumestrol to Bax and Bcl-2, promoting apoptosis initiation.

Conclusions:

• * Coumestrol induces apoptosis in ER-negative breast cancer cells through a mechanism independent of copper and ROS.
• * The primary mechanism involves coumestrol directly interacting with Bax and Bcl-2 proteins, leading to mitochondrial-mediated apoptosis.
• * Coumestrol shows promise as a lead molecule for developing novel targeted therapies for TNBC.