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

Librizzi, Mariangela, Spencer, John and Luparello, Claudio (2016) Biological effect of a hybrid anticancer agent based on kinase and histone deacetylase inhibitors on triple-negative (MDA-MB231) breast cancer cells. International Journal of Molecular Sciences, 17 (8). p. 1235. ISSN 1422-0067

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: John Spencer
Date Deposited: 03 Aug 2016 14:04
Last Modified: 15 Mar 2017 04:28
URI: http://sro.sussex.ac.uk/id/eprint/62212

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