Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs

Abstract

Histone deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval of two HDAC inhibitors, vorinostat and depsipetide, by the FDA. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. However, the molecular mechanisms underlying the response to HDAC inhibitors in cancer patients are not fully understood. In this review, we summarize our understanding of the molecular and biological events that underpin the anticancer effects of HDAC inhibitors and the outcomes of recent clinical trials involving these drugs.

Keywords: HDAC inhibitor; MS-275; acetylation; cancer; depsipeptide (FK228); vorinostat (SAHA).

Figure 1

Structures of major classes of HDAC inhibitors. Suberoylanilide hydroxamic acid (SAHA/Vorinostat/Zolinza), Trichostatin A (TSA), and PXD-101 are hydroxamic acid-based pan-HDAC inhibitors. Depsipeptide (FK228/ romidepsin/ISTODAX®) is a natural cyclic peptide product of prodrug type, which inhibits HDAC1 and 2 selectively. Both MS-275 and MGCD0103 are synthetic benzamide derivatives. MS-275 is selective to HDAC 1, 2, and 3, and MGCD0103 is a class I selective HDAC inhibitor. Aliphatic acids include valproic acid and Sodium phenylbutyrate which have relatively low HDAC inhibitory potency.