Novel combination of salinomycin and resveratrol synergistically enhances the anti-proliferative and pro-apoptotic effects on human breast cancer cells

Abstract

Resveratrol (RES) is a natural polyphenol having anti-proliferative activity against breast cancer cells. RES in combination with other chemo modulatory agents, minimizes toxicity and increases efficacy of the treatment. Salinomycin (SAL), a monocarboxylic polyether ionophore is known for selectively targeting breast cancer stem cells. Purpose of the present study was to investigate whether RES in combination with SAL exerts synergistic anti-proliferative activity on breast cancer cells. We further evaluated the molecular mechanism behind SAL and RES mediated cell death. Cytotoxicity assay was performed to determine 50% inhibitory concentration (IC50) of SAL and RES in different human breast cancer cells (HBCCs). Drug synergism and combination index (CI) were calculated using CompuSyn software and effects of synergistic combinations (CI < 1) involving lower doses of SAL and RES were selected for further studies. This combination significantly induced apoptosis in HBCCs without affecting non tumorigenic human breast epithelial cells MCF-10A. Co-treatment enhanced apoptosis in MCF-7 cells via reactive oxygen species (ROS) mediated mitochondrial dysfunction. Oxidative stress disrupt redox homeostasis which altered antioxidant enzymes viz. CuZn Superoxide dismutase (SOD), MnSOD and catalase. Additionally, combination altered nuclear morphology, enhanced PARP cleavage and led to caspase activation. SAL and RES also synergistically modulated MAPK pathway. Study suggests that SAL and RES offer a novel combination approach for the treatment of breast cancer.

Targeting cancer stem cells and signaling pathways by resveratrol and pterostilbene

“…Studies in recent years elucidated that resveratrol inhibits breast CSCs behavior . For example, Fu et al demonstrated that resveratrol significantly suppressed the proliferation of breast CSCs and lowered the size and number of mammospheres.…”

Resveratrol Inhibits the TGF-β1-Induced Proliferation of Cardiac Fibroblasts and Collagen Secretion by Downregulating miR-17 in Rat

“…RSV is a nonflavonoid polyphenol that is reported to possess antitumor effects, such as promoting apoptosis of human breast cancer cells [31] and inhibiting invasion and migration of pancreatic cancer cells [32]. Additionally, it can inhibit apoptosis, reduce the myocardial infarct size, and protect the cardiovascular system [19, 33].…”

Correlation of Reactive Oxygen Species Levels with Resveratrol Sensitivities of Anaplastic Thyroid Cancer Cells

“…Cellular redox balance is typically maintained by a powerful battery of the antioxidant system in which SOD2 and CAT play active roles [ 11 , 34 ]. Alternatively, reduction of those enzymes may lead to disrupted redox homeostasis, oxidative damage, and finally cell death [ 35 ]. Because of the increased ROS in resveratrol-suppressed THJ-16T but not resveratrol-resistant THJ-11T cells, the statuses of SOD2 and CAT expression in the two cell lines were analyzed in regular intervals after resveratrol treatment.…”