Development of histone deacetylase inhibitors for cancer treatment

Abstract

Histone deacetylase (HDAC) inhibitors are an exciting new addition to the arsenal of cancer therapeutics. The inhibition of HDAC enzymes by HDAC inhibitors shifts the balance between the deacetylation activity of HDAC enzymes and the acetylation activity of histone acetyltransferases, resulting in hyperacetylation of core histones. Exposure of cancer cells to HDAC inhibitors has been associated with a multitude of molecular and biological effects, ranging from transcriptional control, chromatin plasticity, protein–DNA interaction to cellular differentiation, growth arrest and apoptosis. In addition to the antitumor effects seen with HDAC inhibitors alone, these compounds may also potentiate cytotoxic agents or synergize with other targeted anticancer agents. The exact mechanism by which HDAC inhibitors cause cell death is still unclear and the specific roles of individual HDAC enzymes as therapeutic targets has not been established. However, emerging evidence suggests that the effects of HDAC inhibitors on tumor cells may not only depend on the specificity and selectivity of the HDAC inhibitor, but also on the expression patterns of HDAC enzymes in the tumor tissue. In this review, the recent advances in the understanding and clinical development of HDAC inhibitors, as well as their current role in cancer therapy, will be discussed.

Keywords::

• depsipeptide
• HDAC
• HDAC inhibitor
• LBH589
• MGCD0103
• MS-275
• PXD101
• sodium butyrate
• valproic acid
• vorinostat
• zolinza