Literature survey of HDACs in cancer and in-vitro analysis of HDAC inhibitor mediated chemo-sensitization

Abstract

HDACs are chromatin modifying enzymes and post translational modifiers regulating transcription and activity of various proteins such as tubulin, Hsp90 and cortactin respectively. HDAC is divided into four classes (Class 1, Class 2(a, b), Class 3 and Class 4) and 2 families (based on homology) which are Rdp3/Hda1 family and Sirtuin family (NAD+ Dependent Sir2). Tumor cells having no HDACs expression or loss of enzymatic activity due to mutation make them more resistant to HDACi than cells having higher HDAC expression. The objectives of this study were to survey the literature in role of HDACs expression during cancer progression and we found that HDACs are associated with specific cancer types but their appropriate correlation has not been found till now. To analyze the HDAC inhibitor (TSA) mediated chemo-sensitization in doxorubicin treated MDA-MB-231 cells, MTT assay was used to study the chemo-sensitization effect of TSA on cells treated with doxorubicin at different concentrations. We found out that TSA and Doxorubicin alone had higher anti-proliferative effect on MDA-MB-231 cells than other combinatorial doses dependent fashion. None of the above given doses had reduced viability less than 50%, so IC50 value of these given doses are undetermined. 16hrs 100nM TSA treatment followed by 10nM doxorubicin combined had higher anti proliferative effect as compared to other concentration. 16hrs 100nM TSA followed by v 24hrs 10nM doxorubicin treatment results in 30% cell death while for similar experiment at higher concentration of TSA and Doxorubicin, viability is regained in MDA-MB-231 treated cells. This may suggest that TSA in-sensitize/nullified the Doxorubicin induced mitochondrial mediated apoptosis. Combinatorial effect might not be effective in comparison to dual or multi-target inhibitors. HDAC inhibitor mediated chemo-sensitization could be analyzed on other drug treated cancer cell lines. Use of multi-target inhibitor could be seen as effective therapeutic agent against tumor cells.