Mini-reviewHistone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy☆
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
References (73)
- et al.
The hallmarks of cancer
Cell
(2000) - et al.
Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer
J. Biol. Chem.
(2006) - et al.
Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis
Cancer Cell
(2004) - et al.
Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain
Cell
(1997) - et al.
The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress
Cell
(2003) - et al.
HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor
Mol. Cell
(2005) - et al.
E2F family members are differentially regulated by reversible acetylation
J. Biol. Chem.
(2000) HDAC inhibitors: clinical update and mechanism-based potential
Biochem. Pharmacol.
(2007)- et al.
Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance
Blood
(2007) - et al.
Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells
Blood
(2003)
p21Waf1/Cip1 as a therapeutic target in breast and other cancers
Cancer Cell
The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571
Blood
Anticancer activities of histone deacetylase inhibitors
Nat. Rev. Drug Discov.
Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer
Prostate
Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*
Breast Cancer Res. Treat.
HDAC6 expression is correlated with better survival in breast cancer
Clin. Cancer Res.
Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation
Proc. Natl. Acad. Sci. USA
Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation
Proc. Natl. Acad. Sci. USA
Acetylation control of the retinoblastoma tumour-suppressor protein
Nat. Cell. Biol.
Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma
Expert Opin. Investig. Drugs
Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells
Mol. Cancer Ther.
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
Nat. Rev. Cancer
FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells
Oncogene
Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway
Nat. Med.
Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells
Oncogene
Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells
Nat. Med.
HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma
Oncogene
Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228)
J. Cell Physiol.
The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species
Proc. Natl. Acad. Sci. USA
The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells
Mol. Cancer Ther.
Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis
Cell Death Differ.
Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim
Proc. Natl. Acad. Sci. USA
Regulation of p53 responses by post-translational modifications
Cell Death Differ.
The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin
Proc. Natl. Acad. Sci. USA
Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors
Proc. Natl. Acad. Sci. USA
Reactive oxygen species regulate quiescent T-cell apoptosis via the BH3-only proapoptotic protein BIM
Cell Death Differ.
Cited by (386)
Design, synthesis, and biological evaluation of novel HDAC inhibitors with a 3-(benzazol-2-yl)quinoxaline framework
2023, Bioorganic and Medicinal Chemistry LettersSelective inhibition of histone deacetylase 3 by novel hydrazide based small molecules as therapeutic intervention for the treatment of cancer
2022, European Journal of Medicinal ChemistryCurrent paradigms in epigenetic anticancer therapeutics and future challenges
2022, Seminars in Cancer BiologyClinical Applications of Histone Deacetylase Inhibitors
2022, Handbook of Epigenetics: The New Molecular and Medical Genetics, Third EditionHistone deacetylases: A novel class of therapeutic targets for pancreatic cancer
2022, Biochimica et Biophysica Acta - Reviews on Cancer
- ☆
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.