6533b85efe1ef96bd12bfec2

RESEARCH PRODUCT

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

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description

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