The Effect of Histone Deacetylase Inhibitors on Metastatic Breast Cancer Cells in Conjunction with Clinically Relevant Chemotherapeutic Agents

Abstract

Histone Deacetylases (HDACs) are enzymes charged with the job of loosening DNA packaged around histone proteins. This gives them the opportunity to affect the transcriptional regulation of certain cancer associated genes and proteins, but HDACs are not limited to only DNA modification. They also target non-chromatin proteins in the cytoplasm, and have been closely linked to the many pathways involved in metastatic breast cancer such as apoptosis evasion, cell migration, and angiogenesis. HDAC’s effect on important cytoplasmic proteins could play a huge role in the largely unknown mechanisms of metastatic breast cancer. HDAC inhibitors are a rising class of chemotherapeutic agents. In this research, HDAC inhibitors selective for cytoplasmic target proteins are used in conjunction with nuclear based HDAC inhibitors and known microtubule stabilizers and destabilizers to test and explore the effects of HDAC inhibition on MDA-MB-231-derived metastatic breast cancer cell lines BoM-1833 (BoM) and LM-4175 (LM), and in MCF-7-derived metastatic breast cancer cell line MCF-7 BoM. Through viability, clonogenic, and combination assays, the HDAC inhibitors were not found to have complete inhibition of the tumor cells at any of the tested concentrations but show a trend suggesting potential effects on tumor inhibition at higher concentrations. There is also some evidence supporting a potential significance of HDAC inhibitors on ER+ breast cancer cells. Clonogenic assays upheld the inhibitory results of HDAC inhibitors on metastatic breast cancer cells, and emphasized the increased effectiveness of higher concentrations of HDAC inhibitors. Combination assays showed a trend towards antagonistic effects between HDAC inhibitors and microtubule stabilizes