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

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.

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…An important fact was that cell death was induced by both autophagy and apoptosis (69). These results were confirmed by Zhang et al, who used SAHA and the antiangiogenic kinase inhibitor Sorafenib in epithelial tumor cell types and found that this treatment suppressed the expression of anti-apoptotic proteins and increased the activation of CD95 extrinsic apoptotic and lysosomal protease pathways.…”

“…Nevertheless, the majority of studies in the field of TNBC therapy tend to combine HDAC inhibitors with kinase inhibitors, autophagy inhibitors, antibiotics, chemotherapy, IR, or even two HDAC inhibitors treatment in order to enhance their efficacy against TNBC (47,69,71,84,115,123,153). In the majority of the studies, co-treatment of an HDAC inhibitor with another compound induced the inhibition of tumor growth and showed anti-proliferative effects (46,47,77,84,115,123,138,154).…”

Cytotoxic Potential of the Coelomic Fluid Extracted from the Sea Cucumber Holothuria tubulosa against Triple-Negative MDA-MB231 Breast Cancer Cells

“…MDA-MB231 cells are endowed with a constitutively elevated autophagy rate. Inhibition of autophagy was proven to render them susceptible to the lethal effect of chemicals in various experimental conditions (e.g., [18,19,31,32]); on the other hand, lethal effects on this cell line induced by several autophagy inducers have been reported in the literature (e.g., [33,34]).…”

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

“…The goodness of hit score (GH) of this screening protocol was calculated to be 0.796 which indicates the significance of selected pharmacophore to identify active molecules. Further, an external dataset comprising of the known HDAC inhibitors (Librizzi et al, 2016; Patel et al, 2016; Wen et al, 2016; Zhu et al, 2016) that were not included in QSAR model generation and were used as external test set were selected for validating the predictive power of the developed QSAR model. The robustness of the developed QSAR model was analyzed by performing “Y-randomization” test, the low value of $R_{scramble}^2$ (0.629) as compared to $R_{train}^2$ of selected model, described the real regression correlation of the selected model.…”