Cancer Letters

Cancer Letters

Volume 269, Issue 1, 28 September 2008, Pages 7-17
Cancer Letters

Mini-review
Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy

https://doi.org/10.1016/j.canlet.2008.03.037Get rights and content

Abstract

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.

Introduction

Inappropriate gene expression plays an essential role during tumorigenesis and in the progression of cancer [1]. Deacetylation of histones is associated with transcriptional repression, including a decrease in the expression of tumor suppressor genes [2]. Consistent with this observation, histone deacetylases (HDACs) are overexpressed in colon, breast, prostate, and other cancers making them an attractive anticancer target [3], [4], [5], [6], [7]. HDACs have been divided into four classes: Class I (HDAC1, 2, 3, and 8), class IIa (HDAC4, 5, 7, and 9), class IIb (HDAC6 and 10), class III (SIRT1, 2, 3, 4, 5, 6, and 7) and class IV (HDAC11) (Table 1). Class I, II, and IV HDACs are zinc-dependent deacetylases that can be inhibited by broad spectrum HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA, Zolinza®, Vorinostat), trichostatin A (TSA), and LBH589. Class III HDAC-mediated deaetylation is dependent on NAD+. Enzymes of this particular class are not targeted by the aforementioned HDAC inhibitors. Nicotinamide is a potent sirtuin deacetylase (SIRT) inhibitor that blocks their activity by binding to the NAD+ binding pocket. To date, there are no clinically relevant SIRT inhibitors. As such, this review will focus on inhibitors of zinc-containing (class I, II, and IV) HDACs. However, the development of specific inhibitors of SIRT activity is an emerging area of investigation as their inhibition may produce promising anticancer effects.

Since inhibition of HDAC activity can reverse the epigenetic silencing that is frequently observed in cancer, this has led to the development of various HDAC inhibitors for cancer therapy. These include short-chain fatty acids (valproic acid and butyrate), hydroxamic acids (SAHA, TSA, LBH589, PXD101, and tubacin), benzamides (MS-275), and cyclic tetrapeptides (depsipeptide). HDAC inhibitors also have varying degrees of specificity (Table 1). For example, SAHA and LBH589 inhibit all class I, II, and IV HDACs, whereas MS-275 inhibits only HDAC 1, 2, and 3, and valproic acid inhibits HDAC1, 2, 3, 4, 5, 7, 8, and 9 [2]. To date, tubacin is the only isoform-specific HDAC inhibitor developed against HDAC6 [8]. The molecular basis of the anticancer activity of these agents is not completely clear. The creation of more specific inhibitors will enable the different functions of individual HDACs to be more fully elucidated and may also yield improved efficacy along with reduced toxicity.

HDAC inhibitors induce cellular differentiation and strongly promote cell-cycle arrest, typically at the G1/S checkpoint. This effect is most commonly associated with a dramatic increase in p21Waf1/Cip1 due to p53-independent induction of CDKN1A [9]. While stimulating cell-cycle arrest likely contributes to the anticancer activity of HDAC inhibitors, these agents have pleiotropic effects. HDACs also target a number of non-histone proteins such as p53, tubulin, hsp90, Rb, and E2F1 [10], [11], [12], [13], [14]. As such, HDAC inhibitors may have a broader spectrum of activity than initially thought. Consistent with this idea, HDAC inhibitors have demonstrated potent anticancer activity in many pre-clinical models and several agents are currently in clinical trials either as monotherapies or in combination with conventional chemotherapy [15]. Vorinostat is the first HDAC inhibitor approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL) [16]. In addition to Vorinostat, several other HDAC inhibitors are currently being investigated in Phase I and II clinical trials (Table 2) [15]. These drugs may have great clinical utility due to their ability to synergistically enhance the efficacy of many current therapies, including radiation treatment, conventional chemotherapy, and new targeted agents.

Despite the promising anticancer activity of HDAC inhibitors, the mechanisms of HDAC inhibitor-induced cell death are not completely understood. These agents stimulate the accumulation of acetylated histones and non-histone targets that play important roles in cell proliferation, cell death, and gene expression (Table 1). A large number of studies have demonstrated that HDAC inhibitors stimulate apoptosis in a variety cancer models. This review focuses on the mechanisms of HDAC inhibitor-induced apoptosis and other properties that lead to cell death and contribute to their promising anticancer activity when given in combination with other agents.

Section snippets

Mechanisms of HDAC inhibitor-induced cell death

There are two major pathways of apoptosis, the “extrinsic” or death-receptor pathway and the “intrinsic” or mitochondrial pathway. The death-receptor pathway is activated when a ligand such as Fas or Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) bind to their death receptors. This results in the recruitment of the adaptor protein FADD and activation of caspase-8. The mitochondrial pathway is activated by stress stimuli (chemotherapeutic agents) that disrupt the mitochondrial

Mechanisms underlying the anticancer synergy between HDAC inhibitors and other agents

The FDA approval of Vorinostat for the treatment of CTCL demonstrates that targeting HDAC activity is a promising strategy for cancer therapy. Moreover, the therapeutic selectivity of these agents further heightens their clinical appeal. Despite the success of Vorinostat for CTCL, a number of recent studies have suggested that HDAC inhibitors may be most effectively utilized in combination with other chemotherapeutic agents. Many HDAC inhibitors including Vorinostat, depsipeptide, MS-275, and

Conclusions and new directions

Inhibition of HDAC activity promotes gene expression resulting in growth inhibition, differentiation, and apoptosis of cancer cells. Since epigenetic alterations are a hallmark of cancer cells, HDAC inhibitors may have great therapeutic potential. Indeed, Vorinostat was recently approved for the treatment of cutaneous T-cell lymphoma and has demonstrated therapeutic efficacy in other cancer types. HDAC inhibitors induce a diverse array of effects on cancer cells that encourage both cell-cycle

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    This work was supported by funding from The Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio.

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