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Int. J. Mol. Sci. 2016, 17(8), 1235; doi:10.3390/ijms17081235

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

1
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), Edificio 16, Università di Palermo, Viale delle Scienze, Palermo 90128, Italy
2
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
*
Author to whom correspondence should be addressed.
Academic Editors: Atsushi Matsuzawa and Charles J. Malemud
Received: 18 May 2016 / Revised: 20 June 2016 / Accepted: 26 July 2016 / Published: 30 July 2016
(This article belongs to the Special Issue Kinase Signal Transduction)
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Abstract

We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of “aggressive” breast carcinoma. View Full-Text
Keywords: breast cancer; MDA-MB231 cells; histone deacetylase inhibitor; vascular endothelial growth factor receptor-2 inhibitor; cytotoxicity; cell cycle; apoptosis; autophagy; mitochondrial metabolism breast cancer; MDA-MB231 cells; histone deacetylase inhibitor; vascular endothelial growth factor receptor-2 inhibitor; cytotoxicity; cell cycle; apoptosis; autophagy; mitochondrial metabolism
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Librizzi, M.; Spencer, J.; Luparello, C. Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells. Int. J. Mol. Sci. 2016, 17, 1235.

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