Abstract
We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor Pojamide (N1-(2-aminophenyl)-N8-ferrocenyloctanediamide) and its two derivatives N1-(2-aminophenyl)-N6-ferrocenyladipamide and N1-(2-aminophenyl)-N8-ferroceniumoctanediamide tetrafluoroborate on triple-negative MDA-MB-231 breast cancer cells. Viability/growth assays indicated that only the first two compounds at 70 μM concentration caused an approximate halving of cell number after 24 h of exposure, whereas the tetrafluoroborate derivative exerted no effect on cell survival nor proliferation. Flow cytometric and protein blot analyses were performed on cells exposed to both Pojamide and the ferrocenyladipamide derivative to evaluate cell cycle distribution, apoptosis/autophagy modulation, and mitochondrial metabolic state in order to assess the cellular basis of the cytotoxic effect. The data obtained show that the cytotoxic effect of the two deacetylase inhibitors may be ascribed to the onset of non-apoptotic cell death conceivably linked to a down-regulation of autophagic processes and an impairment of mitochondrial function with an increase in intracellular reactive oxygen species. Our work expands the list of autophagy-regulating drugs and also provides a further example of the role played by the inhibition of autophagy in breast cancer cell death. Moreover, the compounds studied may represent attractive and promising targets for subsequent molecular modeling for anti-neoplastic agents in malignant breast cancer.
Highlights
Histone deacetylases (HDAC) are enzymatic epigenetic modulators whose involvement in the modification of chromatin structure and regulation of the activity of many non-histone proteins is widely recognized
Only four HDAC inhibitors (HDACi) have been approved by the U.S Food and Drug Administration, a great number of them are undergoing clinical trials in order to thoroughly exploit their full potential as anticancer agents [3,4]
In the first set of experiments, we checked the effect of dose- and time-dependent incubation with either 1, 2, or 3 on MDA-MB-231 cell viability via direct cell counting and MTS assay
Summary
Histone deacetylases (HDAC) are enzymatic epigenetic modulators whose involvement in the modification of chromatin structure and regulation of the activity of many non-histone proteins is widely recognized They are grouped into four classes on the basis of functional criteria and homology to yeast proteins; they show distinct gene expression patterns, intracellular localization, and role [1]. HDAC inhibition is known to affect several intracellular processes, such as gene expression, signal transduction, and protein turnover, and to alter the proliferation, survival, and immunogenicity of cancer cells. Within this context, HDAC inhibitors (HDACi) are an emerging class of heterogeneous compounds that are grouped into different categories on the basis of their chemical nature. Increasing knowledge of the distinct pathways that are involved in tumor growth or metastasis in different neoplastic histotypes has emphasized the need to develop selective agents that target individual HDACs and the investigation, at the molecular level, of the biological response to such selective inhibitors by cancer cells
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