Biological effect of a hybrid anticancer agent based on kinase and histone deacetylase inhibitors on triple-negative (MDA-MB231) breast cancer cells

摘要

We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilideudhydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitorud(3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breastudcancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemicallyudsynthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-ud5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed onudcocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation,udand mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect.udCell cycle analysis showed a perturbation of the rate of progression through the cycle, withudaspects of redistribution of cells over different cycle phases for the two treatments. In addition,udthe results suggest that the two distinct classes of compounds under investigation could induceudcell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosisudpromotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. theudcombination approach in finely tuning the biological activities of target cells and also showing theudhybrid compound as an additional promising drug-like molecule for the prevention or therapy ofud“aggressive” breast carcinoma.