HDAC Inhibitors (Vorinostat) As A Potential Therapy for Metastatic Breast Cancer

Abstract

Background. Histone deacetylase inhibitors (HDACi) are an emerging group of compounds with significant chemotherapeutic potential. The hydroxamic acid and suberanilohydroxamic acid (SAHA) are currently in trials for breast cancer. HDACi, including SAHA, entinostat, panobinostat and butyrate, have previously been shown to induce apoptosis and cell cycle arrest of breast cancer cells, and there are suggestions that HDACi may also inhibit the production of the hypoxia inducible factor (HIF-1α) thereby potentially inhibiting the response of breast cancer cells to hypoxia. The current study aims to establish whether HDACi (SAHA) will inhibit breast cancer cell activity under hypoxic conditions. Methods. MCF7 and MDA-MB-231 Cells were cultured in both normoxia and hypoxia (1% O2) environments in the presence of SAHA (0.5-20mM) for up to 72 hours. Proliferation was then established using the MTS assay. Result. SAHA could inhibit breast cancer cell proliferation under hypoxic (1% O2) conditions in a dose dependent manner. In normoxia, the MDA-MB-231 (high metastatic potential, ER negative) were more sensitive than MCF-7 (low metastatic potential, ER positive) in contrast to hypoxia where MCF-7 were more responsive to SAHA than under normoxia, compared to MDA-MB- 231 which were less responsive compared to normoxia. Conclusion. The obtained data have important therapeutic implications as many current chemotherapies have no effect in hypoxic tumours.