Protein Function Inhibitors / HDAC inhibitors / Mechanism
HDAC inhibitors: ROMIDEPSIN, VORINOSTAT
Mechanism
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histone deacetylases (HDACs) work in conjunction with histone acetyltransferases to regulate gene expression- acetylation is associated with euchromatin ("open for transcription")
- deacetylation is associated with heterochromatin ("closed")
- some cancer cells overexpress or aberrently recruit HDACs, leading to hypoacetylation of histones, condensed chromatin structure and decreased transcription
- causes silencing of tumor suppressor genes (esp. p53)
- HDAC inhibitors increase transcription, and lead to cell cycle arrest and apoptosis
- valproic acid (a 1st generation HDAC inhibitor that is approved for use as a mood stabilizer and as an antiepileptic) is under investigation for use in cancer
- HDAC inhibitors are also under active investigation for use in Huntington's disease and ALS
- VORINOSTAT is approved for use in cutaneous T-cell lymphoma, and is under investigation in glioblastoma multiforme and HIV
- VORINOSTAT undergoes hepatic metabolism (but not by CYP450), and it is not a substrate for P-glycoprotein