Histone Deacetylase Inhibitors

Histone Deacetylase Inhibitors. Histone deacetylase (HDAC) inhibitors are responsible for inhibiting histone deacetylase enzymes, which work to remove acetyl groups from histones. The overexpression of HDACs is responsible for many cancers such as prostate, colorectal, breast, lung, liver, and gastric cancer. Currently, four drugs are FDA approved to function as HDAC inhibitors: Vorinostat (2006), Romidepsin (2009), Chidamide (2015), and Panobinostat (2015). Vorinostat is a linear hydroxamic acid compound used against refractory cutaneous T cell lymphoma as a broad inhibitor of class I and II HDACs. By binding to the active site of class I and II HDACs, Vorinostat is able to induce the accumulation of acetylated histones and thus inducing …show more content…
Romidepsin is a bicyclic compound that acts as a prodrug within the body. A prodrug is a drug that is originally inactive until the body metabolizes it and turns it active. In the case of Romidepsin, glutathione in the body’s cells reduce the drugs disulfide bridges, thus allowing the free sulfur groups (forming thiols) to interact with zinc ions in class I and II HDAC’s active sites. Romidepsin can have multiple target genes, however the most important one found is p21, a tumor-suppressor gene. Romidepsin acts to induce the expression of p21, which would have otherwise been de-acetylated and under-expressed. This induction of p21 leads to the inhibition of cyclin-depedent kinase (CDK) and the dephosphorylation of retinoblastoma protein, which ultimately leads to cell cycle arrest in the G1 phase. Chidamide and Panobinostat are both newly approved drugs by the FDA. Chidamide acts to inhibit the growth of tumor cells by epigenetic regulation of HDACs, causing the regulation of the cell cycle and even apoptosis for patients with pancreatic cancer. Panobinostat, similarly, can act to arrest the cell cycle and also cause caspase dependent and independent apoptosis in patients with multiple