Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy.
Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression by catalyzing the removal of acetyl groups, stimulating chromatin condensation and promoting transcriptional repression. Since aberrant epigenetic changes are a hallmark of cancer, HDACs are a promising target for pharmacological inhibition. HDAC inhibitors can induce cell-cycle arrest, promote differentiation, and stimulate tumor cell death. These properties have prompted numerous preclinical and clinical investigations evaluating the potential efficacy of HDAC inhibitors for a variety of malignancies. The preferential toxicity of HDAC inhibitors in transformed cells and their ability to synergistically enhance the anticancer activity of many chemotherapeutic agents has further generated interest in this novel class of drugs. Here we summarize the different mechanisms of HDAC inhibitor-induced apoptosis and discuss their use in combination with other anticancer agents.
Carew
Jennifer S
JS
The Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 14960 Omicron Drive, San Antonio, TX 78245, USA.
Giles
Francis J
FJ
Nawrocki
Steffan T
ST
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib