Histone Deacetylase Inhibitors in Cancer Therapy

Abstract

Histone deacetylase inhibitors (HDAC inhibitors) represent a novel class of antineoplastic agents that act by promoting acetylation of histones, leading in turn to uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell surivival, proliferation, differentiation, and apoptosis. The major classes of HDIs include shortchain fatty acids, hydroxamic acid derivatives, synthetic benzamide derivatives, and cyclic tetrapeptides. Members of each of these classes have now entered clinical trials in humans. Despite their shared capacity to trigger histone deacetylation, individual HDIs exert diverse actions on cell cycle regulatory, signal transduction, and survival-related proteins which in all probability accounts for their disparate actions. Major areas of investigation surrounding HDIs include elucidating the mechanisms by which they induce apoptosis in neoplastic cells, and characterizing the factors responsible for the decision of such cells to undergo maturation versus cell death in the response to these agents. In this context, attention has recently focused on the ability of HDIs to induce perturbations in cell cycle regulatory proteins (e.g., p21(CIP1)), downregulation of survival signaling pathways (e.g., Raf/MEK/ERK), and disruption of cellular redox state (e.g., induction of reactive oxygen species; ROS). Aside from efforts to combine HDIs with established cytotoxic drugs, attempts are underway to establish a rational basis for combining HDIs with differentiation- inducing agents (e.g., ATRA, hypomethylating agents such as 5'-deoxyazacytine) with the goal of triggering re-expression of turn or suppressor and/or differentiation-associated genes. Finally, the results of recent preclinical studies provide a strong rationale for combining HDIs with other novel, molecularly targeted agents, including inhibitors of survival signaling pathways or cell cycle progression. Collectively, these findings should provide a fertile environment for the development of novel HDI-containing regimens in the treatment of cancer for many years to come.

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

“…However, the mechanism by which HDAC inhibitors induce apoptosis is still not completely understood and includes activation of either caspase-dependent or caspase-independent pathways (Rosato et al, 2003). Apicidin causes the death of HL60 through de nove synthesis of Fas/Fas ligand and activation of the extrinsic/ receptor mediated caspase pathway (Kwon et al, 2002).…”

Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines

“…Because histone deacetylase inhibitors are being tested as new antineoplastic agents (36,37), we have analyzed the effects of two histone deacetylase inhibitors, TSA and SAHA, in three different human pancreatic adenocarcinoma cell lines, IMIM-PC-1, IMIM-PC-2, and RWP-1. The aim of our study was to determine whether histone deacetylase inhibitors can be considered as effective antitumor drugs against pancreatic cancer.…”

Prospects: Histone deacetylase inhibitors

“…Structural alterations in HDACs associated with cancers appear to be rare. HDACs are involved in the function of oncogenic translocation products in specific forms of leukemia and lymphoma [Rosato and Grant, 2003;Marks et al, 2004;Drummond et al, 2005]. The oncoprotein that is encoded by one of the translocation-generated fusion genes in acute promyelocytic leukemia, PML-RARa, represses transcription by associating with a corepressor complex that contains HDAC activity.…”

“…Unlike the alterations in HDACs associated with neoplasms, structural alterations in HATs, including translocations, amplifications, deletions and point mutations have been found in various human cancers-both hematological and epithelial [Lehrmann et al, 2002;Rosato and Grant, 2003;Lindemann et al, 2004;Marks et al, 2004;Drummond et al, 2005]. For example, the HATs, CBP and p300, are altered in some tumors by mutation or translocation.…”