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 Jul 30;17(8):1235. doi: 10.3390/ijms17081235.

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.

Keywords: MDA-MB231 cells; apoptosis; autophagy; breast cancer; cell cycle; cytotoxicity; histone deacetylase inhibitor; mitochondrial metabolism; vascular endothelial growth factor receptor-2 inhibitor.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Survival / drug effects*
  • Female
  • Flow Cytometry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Indoles / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / pathology*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vorinostat

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • N-hydroxy-N'-(2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl)octanediamide
  • Protein Kinase Inhibitors
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Vorinostat