Histone Deacetylase Inhibitors

Abstract

Histone deacetylase (HDAC) inhibitors are a new group of anticancer agents that have a potential role in the regulation of gene expression, induction of cell death, apoptosis and cell cycle arrest of cancer cells by altering the acetylation status of chromatin and other non-histone proteins. In clinical trials, HDAC inhibitors have demonstrated promising antitumour activity as monotherapy in cutaneous T-cell lymphoma and other haematological malignancies. In solid tumours, several HDAC inhibitors have been shown to be efficacious as single agents; however, results of most clinical trials were in favour of using HDAC inhibitors either prior to the initiation of chemotherapy or in combination with other treatments. Currently, the molecular basis of response to HDAC inhibitors in patients is not fully understood. In this review, we summarize the current status of HDAC inhibitors, as single agents or in combination with other agents in different phases of clinical trials. In most of the clinical trials, HDAC inhibitors were tolerable and exerted biological or antitumor activity. HDAC inhibitors have been studied in phase I, II and III clinical trials with variable efficacy. The combination of HDAC inhibitors with other anticancer agents including epigenetic or chemotherapeutic agents demonstrated favourable clinical outcome.

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“…Some studies have shown that the decrease in HDAC activity is associated with the suppression of tumor cell growth [55,56]. In a variety of tumors, the change to a greater state of acetylation, as a result of HDAC inhibition, can result in modification of the expression of several genes.…”

Histone deacetylase inhibitors: A chemical genetics approach to understanding cellular functions

“…HDAC2 is a regulator of chromatin compaction status and its down-regulation or inhibition causes chromatin decondensation and sensitization to DNA targeted anti-cancer drugs (19). Class II HDACs have more tissue specific regulatory functions (Table 1) (4, 8, 14). HDAC1 knock-out is an embryonic lethal by day 9.5 and results in proliferation defects of embryonic stem cells (20).…”

“…A number of recent papers have reviewed the current status of clinical trials with HDAC inhibitors as monotherapy and combination for cancers (4, 8-12). …”

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“…[1][2][3][4][5] HDAC inhibitors (HDACi) exert a wide range of anticancer effects including induction of cell cycle arrest, promotion of apoptosis (extrinsic and intrinsic), inhibition of DNA damage repair, blockage of angiogenesis, and inhibition of metastasis. 1,6 Their mechanism of action, resulting from the modulation of gene and protein function, affects cellular processes that form the basis of cancer cell malfunctioning and presumably can also affect the activity of conventional drugs, rendering them ideal candidates for combination strategies. Indeed, there are a growing number of reports on the additive or synergistic effects when HDACi are combined with other cytotoxic or targeted therapeutics including several preclinical studies.…”