Disafynol: A polyacetylene dimer from Centaurea schmidii enhancing breast cancer cell apoptosis via oxidative and ER stress pathways.

Abstract

Phytochemical analysis of the aerial parts of Centaurea schmidii Wagenitz (Asteraceae) led to the isolation of disafynol, a novel polyacetylene, for the first time. This study investigated its anti-cancer effects and the mechanisms underlying these effects in MDA-MB-231 (estrogen receptor-negative) and MCF-7 (estrogen receptor-positive) breast cancer cell lines. The cytotoxic effects of disafynol were evaluated using various concentrations to measure cell viability, apoptosis, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), caspases-12/6 activity, and protein aggregation. Expression of apoptotic markers and endoplasmic reticulum (ER) stress-related genes was analyzed by western blot and reverse transcription-PCR analyses, respectively. Disafynol exhibited dose-dependent cytotoxicity, with greater potency in MDA-MB-231 cells (IC50: 10.6 µM) compared to MCF-7 cells (IC50: 30 µM), indicating hormone receptor-independent manner of cell growth inhibition. Treating cells with disafynol caused significant apoptosis, marked by enhanced ROS production and reduced MMP. Meanwhile, disafynol induced Bcl-2 downregulation, Bax upregulation, and caspase-12/6 activities in both breast cancer cells. Additionally, disafynol triggered ER stress, as evidenced by protein aggregation and upregulation of genes related to ER stress, including BIP, ATF4, CHOP, and XBP-1. Overall, disafynol demonstrates significant pro-apoptotic effects on breast cancer cells by inducing oxidative stress and activating the ER stress pathway. Its hormone receptor-independent cytotoxicity suggests potential therapeutic applications for treating breast cancers, including triple-negative subtypes.