In addition to well-characterized genetic abnormalities that lead to cancer onset and progression, it is now recognized that alterations to the epigenome may also play a significant role in oncogenesis. As a result, epigenetic-modulating agents such as histone deacetylase inhibitors (HDACi) have attracted enormous attention as anticancer drugs. In numerous in vitro and preclinical settings, these compounds have shown their vast potential as single agent anticancer therapies, but unfortunately equivalent responses have not always been observed in patients. Given the pleiotropic effects HDACi have on malignant cells, their true therapeutic potential most likely lies in combination with other anticancer drugs. In this review we will focus on the anticancer effects of HDACi when combined with other cancer therapeutics with an emphasis on those combinations based on a strong molecular rationale.

Cancer is a disease caused by insult to the normal genome and it is apparent that both genetic and epigenetic alterations can play a critical role in tumor initiation and progression (13). Compounds targeting enzymes such as histone deacetylases (HDAC) that are actively involved in chromatin remodeling and have been shown to be aberrantly expressed and/or inappropriately activated or localized in human tumors have generated great interest as anticancer drugs (4, 5). Indeed, treatment of malignant cells with HDAC inhibitors (HDACi) can induce a range of anticancer effects including tumor cell apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune responses, and altered angiogenesis (5). As a consequence of their therapeutic potential in laboratory studies, the single-agent activities of numerous HDACi have been tested in the clinic or are currently the subject of ongoing early-phase clinical trials (6, 7). As monotherapies, HDACi have thus far been shown to be effective against a defined subset of hematological tumors however there is less than convincing evidence that these agents will be effective against solid tumors as single agents (8, 9).

Considering the diverse anticancer effects mediated by HDACi and their moderate and largely manageable clinical side effects, the full therapeutic potential of HDACi will probably be best realized through combination with other anticancer agents. There have been numerous reports documenting the enhanced antitumor effects (predominantly enhanced apoptosis) of combining HDACi with a vast array of cancer therapeutics in studies done in vitro with human or mouse tumor cell lines (5, 7). The agents tested in combination with HDACi range from traditional anticancer agents such as cytotoxic drugs and γ-irradiation to small molecule inhibitors of defined molecular cancer targets (5). Most of the published reports do not provide a preconceived molecular rationale for combining an HDACi with a given agent(s). Moreover, the molecular and biological events that underpin any observed additive or synergistic combination effect are largely ill-defined. As a result, it is clear that HDACi can augment the antitumor activities of a plethora of pharmacological and biological anticancer agents, however little is known about how this occurs, and accordingly, there is little useful information to direct the future clinical use of HDACi in combination with other agents.

In this review, we will summarize current data on combination strategies that utilize HDACi. We will focus on those studies in which a rationale for combining a given HDACi with another agent is apparent and those studies that provide preclinical and/or clinical trial data.

HDACi and modulators of transcription. The promoter regions of genes that play important roles in regulating cell cycle, apoptosis, DNA repair, differentiation, and cell adhesion are often hypermethylated and therefore transcriptionally silenced in tumors, and this provides strong circumstantial evidence that aberrant epigenetic control may be an important oncogenic event (3, 10). Abnormal patterns of DNA methylation in tumors can occur either as a result of overexpression of DNA methyltransferases (DNMTs) or the inappropriate recruitment of these enzymes to promoters (11), and transcriptional silencing via DNA hypermethylation can often be associated with poor clinical outcome (3, 12). If we accept that tumor-selective silencing of tumor suppressor genes is an oncogenic driver, then targeting the reexpression of these genes is a logical therapeutic approach. Although inhibition of DNMT activity using pyrimidine nucleoside analogs such as decitabine (Dacogen, SuperGen, Inc.) and azacitidine (Vidaza, Celgene) can result in the reexpression of hypermethylated genes, this response is greatly enhanced through the combined effects of HDACi and DNMT inhibitors (DNMTi; refs. 13, 14) (Fig. 1A). Indeed this strategy has proven successful in vitro with the combination of HDACi and DNMTi demonstrating enhanced anticancer responses (15, 16). Among the reactivated genes are tumor suppressor genes such as CDKN1A, CDKN2A, and CDKN2B encoding the cyclin-dependent kinase inhibitors p21, p16, and p15, respectively (13, 17, 18).

Fig. 1.

HDAC inhibitors act synergistically with anticancer drugs by various mechanisms. A, combination strategies acting via transcription. i, hypermethylation of genes is an often-observed mechanism to silence transcription of target genes. DNA demethylation using DNMT inhibitors in combination with hyperacetylation of histone proteins results in a more “open” chromatin structure mediating enhanced gene transcription. ii, PML-RARα bound to a retinoic acid response element (RARE) recruits an HDAC-containing repressor complex resulting in transcriptional repression. HDAC inhibitors and retinoic acid (RA) induce dissociation of the repressor complex, recruitment of coactivators with histone acetyltransferase (HAT) activity, increased levels of histone acetylation, chromatin remodeling, and transcriptional activation. B, combination strategies modulating protein degradation. i, in absence of normal proteosome function, such as in presence of bortezomib, misfolded proteins are degraded via formation of aggresome. This pathway depends on the deacetylation of α-tubulin via HDAC6. Inhibition of HDAC6 by HDAC inhibitors prevent processing of aggresomes, results in ER stress and subsequent apoptosis. ii, heat shock proteins such as Hsp90 are important in stabilizing client proteins such as the oncoproteins Bcr-Abl and mutated c-kit. Following acetylation of Hsp90 client proteins are released from the Hsp90 chaperone and degraded by the proteosome, resulting in apoptosis. This effect can be enhanced by addition of Hsp90 inhibitor 17-AAG. C, acetylation of both histone and nonhistone proteins results in change in the expression and activity of apoptotic proteins that favors a proapoptotic response and a lowering of the cellular apoptotic threshold. In general proapoptotic proteins only such as BH3 are upregulated whereas antiapoptotic proteins such as c-FLIP are downregulated. These cells are therefore sensitized to apoptosis induced by death receptor ligands (i.e., TRAIL) and prosurvival Bcl-2 family antagonists (i.e., ABT-737). Me, methylated; Ac, acetylated; Ub, ubiquitinated.

Fig. 1.

HDAC inhibitors act synergistically with anticancer drugs by various mechanisms. A, combination strategies acting via transcription. i, hypermethylation of genes is an often-observed mechanism to silence transcription of target genes. DNA demethylation using DNMT inhibitors in combination with hyperacetylation of histone proteins results in a more “open” chromatin structure mediating enhanced gene transcription. ii, PML-RARα bound to a retinoic acid response element (RARE) recruits an HDAC-containing repressor complex resulting in transcriptional repression. HDAC inhibitors and retinoic acid (RA) induce dissociation of the repressor complex, recruitment of coactivators with histone acetyltransferase (HAT) activity, increased levels of histone acetylation, chromatin remodeling, and transcriptional activation. B, combination strategies modulating protein degradation. i, in absence of normal proteosome function, such as in presence of bortezomib, misfolded proteins are degraded via formation of aggresome. This pathway depends on the deacetylation of α-tubulin via HDAC6. Inhibition of HDAC6 by HDAC inhibitors prevent processing of aggresomes, results in ER stress and subsequent apoptosis. ii, heat shock proteins such as Hsp90 are important in stabilizing client proteins such as the oncoproteins Bcr-Abl and mutated c-kit. Following acetylation of Hsp90 client proteins are released from the Hsp90 chaperone and degraded by the proteosome, resulting in apoptosis. This effect can be enhanced by addition of Hsp90 inhibitor 17-AAG. C, acetylation of both histone and nonhistone proteins results in change in the expression and activity of apoptotic proteins that favors a proapoptotic response and a lowering of the cellular apoptotic threshold. In general proapoptotic proteins only such as BH3 are upregulated whereas antiapoptotic proteins such as c-FLIP are downregulated. These cells are therefore sensitized to apoptosis induced by death receptor ligands (i.e., TRAIL) and prosurvival Bcl-2 family antagonists (i.e., ABT-737). Me, methylated; Ac, acetylated; Ub, ubiquitinated.

Close modal

It is currently not known if the reactivation of epigenetically silenced genes is the molecular event that underpins the antitumor effects observed when DNMTi and HDACi are combined, and if so, if specific reactivation of only one or a number of epigenetically silenced genes is necessary.

There is a strong molecular rationale for combining HDACi and all-trans retinoid acid (ATRA) for the treatment of acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML; refs. 19, 20). These tumors often harbor either the oncogenic fusion protein PML-RARα or PLZF-RARα that results in abnormal recruitment of HDAC-containing repressor complexes to retinoic acid response elements (RAREs). Although APL can often be highly sensitive to treatment with ATRA concomitant with release of repressor complexes from retinoic acid response (RAR)α, leukemias driven by PLZF-RARα and certain PML-RARα variants can be relatively unresponsive to ATRA. Combination with HDACi however results in the release of the repressor complexes and restores the sensitivity to ATRA (Fig. 1A). The combination of HDACi and retinoids has been successfully shown in vitro and in vivo in experimental models (2022). Consistent with these preclinical findings, treatment with ATRA and the HDACi sodium phenylbutyrate induced a clinical response in a retinoic acid-resistant APL patient (23). Although retinoids have some clinical benefit for the treatment of neuroblastoma, intrinsic and acquired resistance to this form of therapy has been observed (24). As such it was hypothesized that combination therapy using HDACi and retinoids may be effective for the treatment of neuroblastoma and encouraging results have been obtained in preclinical studies (2527). Although HDACi treatment increases the expression of retinoic acid receptor beta (RARβ; ref. 28) and RAR genes are certainly activated following combination treatment, it remains unclear if the activation of RAR genes is necessary for the observed combination effect.

In addition to histones, a range of cellular proteins are posttranslationally modified by HDACs resulting in their altered function, stability, or cellular localization (5, 29). As such, in addition to HDACi-induced anticancer effects caused by altered gene transcription, the biological activities of HDACi may be mediated by functional changes to nonhistone proteins such as transcription factors (e.g., p53, Bcl6, E2F1), DNA repair proteins (e.g., Ku70), cytoskeletal proteins (e.g., α-tubulin), and chaperone proteins (e.g., Hsp90; ref. 29).

The accumulation of misfolded and damaged proteins that can be toxic to cells is circumvented through their removal either through the activity of chaperones such as Hsp90 and/or through the transportation of protein aggregates from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed (30). This processing of misfolded and/or damaged proteins may be particularly important for tumor cells that produce large amounts of these aberrant proteins. HDAC6 plays a key role in the misfolded protein response by deacetylating Hsp90, resulting in the stabilization of client proteins that can include overexpressed (i.e., ErbB2/Her2), fusion (i.e., Bcr-Abl), and mutated (i.e., c-kit, FLT3) oncoproteins, the expression of which tumor cells can often be reliant on (“addicted”) for their growth and survival (Fig. 1B; refs. 31, 32). Moreover, HDAC6 plays an important role in the aggresome pathway through its ability to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes (Fig. 1B; ref. 33). Accordingly, tumor cells are potentially vulnerable to HDAC6 inhibition and this has been exploited by combining HDACi with Hsp90 inhibitors such as 17-allyl-amino-demethoxy geldanamycin (17-AAG; refs. 3437) and with proteosome inhibitors such as bortezomib (Velcade, Millennium Pharmaceuticals; refs. 3841). In addition, the combined effect of directly targeting oncogenic client proteins such as ErbB2/Her2 and Bcr-Abl using Herceptin and Imatinib respectively and destabilizing these proteins through hyperacetylation of Hsp90 by HDACi has a potent antitumor effect in vitro (4244). Although it is tempting to speculate that targeting the misfolded protein response pathway at two points (Hsp90 and the aggresome pathway) by inhibition of HDAC6 is the molecular event necessary for the observed effects of combining HDACi with agents such as 17-AAG and bortezomib, romidepsin has higher affinity for HDAC1 and 2 than HDAC6 (45), yet this HDACi can also function synergistically with proteosome inhibitors (46, 47) indicating that other HDACs may be involved in the combined antitumor responses.

HDACi are potent inducers of tumor cell apoptosis and recent preclinical studies have defined a direct correlation between the ability of HDACi to kill tumor cells, and therapeutic efficacy (4850). It was recently shown that constitutive Janus-activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling may be useful as a biomarker for nonresponsiveness in patients with cutaneous T-cell lymphoma (CTCL) receiving the HDACi vorinostat as part of a phase IIb clinical trial. Decreased expression of antiapoptotic proteins following inhibition of JAK activity sensitized previously resistant CTCL cells to vorinostat-mediated apoptosis (51). This observation provides circumstantial evidence that although HDACi can elicit a range of biological responses that may affect tumor growth and/or survival, direct tumor cell apoptosis induced by HDACi is likely to play a very important role in mediating the therapeutic responses observed. Therefore there exists a strong impetus to design combination strategies aimed at augmenting HDACi-mediated death of tumor cells as detailed below (Fig. 1C).

HDACi and death receptor agonists. HDACi can increase the expression and/or activity of proteins that directly transmit an apoptotic signal through death receptor pathways such as death receptors [i.e., Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptors], death receptor ligands (i.e., Fas ligand, TRAIL), and downstream caspases (caspase-8 and -3), and can downregulate proteins that negatively regulate death-receptor signaling (i.e., c-FLIP, XIAP, survivin, c-IAP1/2; refs. 5, 50, 5257). These results provides a strong rationale to combine HDACi with death receptor stimuli and given the tumor-selective activity attributed to TRAIL and agonistic anti-TRAIL receptor antibodies and their clinical development as anticancer agents (see ref. 58 and references therein), this combination seems most attractive. In vitro studies have shown that sublethal doses of HDACi can sensitize tumor cells to TRAIL-mediated apoptosis (58) and importantly, HDACi do not sensitize normal cells to TRAIL-mediated apoptosis (59). We have recently extended the synergistic antitumor activity of HDACi and agonistic anti-TRAIL receptor antibodies (MD5-1) observed in vitro to significant therapeutic responses in vivo. Complete regression of established syngeneic breast cancers was observed using a vorinostat/MD5-1 combination, whereas either agent used alone caused only a minimal delay in tumor growth (60). Interestingly, synergistic tumor cell apoptosis mediated by vorinostat and MD5-1 was concomitant with proteosome-mediated downregulation of c-FLIP with no change in TRAIL, TRAIL-receptor, or death receptor regulatory proteins observed (60).

HDACi and inhibitors of prosurvival Bcl-2 proteins. Overexpression of prosurvival Bcl-2 proteins (Bcl-2, Bcl-XL, Mcl-1, Bcl-w, and A1) is commonly observed in tumor cells and is associated with resistance to apoptosis mediated by chemotherapeutic drugs (61). These proteins play a major role in the regulation of the intrinsic apoptosis pathway by preventing mitochondrial outer membrane permeabilization and the release of mitochondrial proteins such as cytochrome c and smac/DIABLO (62). Although the finding that overexpression of Bcl-2 family proteins can potently inhibit HDACi-mediated apoptosis in vitro has been well-established (see ref. 5 and references therein), we have shown that these proteins can also inhibit the therapeutic activities of HDACi in preclinical cancer models (48, 49). Most recently, we have shown that ABT-737, a small molecule inhibitor of Bcl-2 can resensitize Bcl-2-overexpressing, HDACi-resistant tumors to HDACi-mediated apoptosis in vitro and in vivo (63). Our demonstration that a significant decrease in tumor burden was achievable in mice following only a single treatment with ABT-737 and vorinostat raises the exciting possibility that this therapeutic regimen may be developed for clinical application. ABT-263 is an orally bioavailable homolog of ABT-737 that as detailed below is currently under investigation in early phase clinical trials as an anticancer agent (6467) indicating that combination studies using HDACi and ABT-263 in human patients may be achievable in the near future.

As outlined in the previous section, many different combination strategies using HDACi have been successfully tested in laboratory studies. Based on these findings, it is not surprising that many trials have been started to test their safety and efficacy in clinical settings. Initial studies concentrated on combining HDACi with Food and Drug Administration (FDA)-approved, clinically validated chemo- and radio-therapeutics to augment their anticancer activities (8, 9). In addition, clinical studies using HDACi in combination with targeted therapeutics including those outlined above have been initiated (Table 1). Among these therapeutics are bortezomib, azacitidine, and decitabine, which all have already been approved by the FDA for treatment of multiple myeloma and myelodysplastic syndromes respectively. Although most of the clinical trials are still ongoing and concentrate predominantly on dosing schedule and safety of the combination therapies, so far some studies have shown encouraging results. In patients with advanced hematological or solid malignancies the combination of DNMTi and HDACi was well tolerated and showed biological effects such as DNA hypomethylation and histone acetylation (6874). Importantly, this combination strategy showed clinical activity and in at least one preliminary study vorinostat in combination with azacitidine seems to be more effective compared with azacitidine alone (74). Although these data support further investigation, especially to evaluate the clinical efficacy of these combinations in randomized trials, it has to be noted that this strategy also resulted in some unfavorable outcomes and HDACi combined with DNMTi was dose-limited by encephalopathy (75). Such neurologic effects seem to be common adverse events following treatment with structurally diverse HDACi although the cause of these side effects is unknown (8). Compared with DNMTi, only limited data are available combining proteosome inhibitors such as bortezomib and NPI-0052 with HDACi. Results to date indicate that these combinations are well tolerated and seem to be clinically effective in both solid tumors and multiple myeloma (76, 77).

Table 1.

Active clinical trials using HDACi in combination with other agents

HDACiSynonymPhaseCombination drug(s)Indication
Vorinostat SAHA Azacitidine Nasopharyngeal carcinoma, lymphoma 
  Decitabine Advanced solid tumors, lymphoma, leukemia 
  Decitabine Hematologic cancer or other diseases 
  Decitabine Myelodysplastic syndromes, AML 
  Bortezomib Lung cancer 
  Bortezomib Metastatic solid tumors 
  Bortezomib Advanced lung cancer 
  Bortezomib Advanced multiple myeloma 
  NPI-0052 Lung cancer, pancreatic cancer, melanoma, lymphoma 
  I/II Azacitidine Myelodysplastic syndromes, AML 
  II Bortezomib Recurrent glioblastoma multiforme 
  II Bortezomib Recurrent lymphoma 
  II Bortezomib Refractory multiple myeloma 
  III Bortezomib Multiple myeloma 
Entinostat MS-275 Azacitidine Leukemia; myelodysplastic syndromes 
  I/II Azacitidine Lung cancer 
  II Azacitidine Leukemia; myelodysplastic syndromes 
Panobinostat LBH589 Bortezomib Multiple myeloma 
  I/II Decitabine Myelodysplastic syndromes, AML 
Valproic acid Valproate Azacitidine Advanced cancers 
  Decitabine Leukemia; lymphoma 
  Decitabine Lymphoma 
  Decitabine Lung cancer 
  II Decitabine Myelodysplastic syndromes; leukemia 
  I/II Azacitidine; ATRA Myelodysplastic syndromes; leukemia 
  II Azacitidine; ATRA Myelodysplastic syndromes 
  II Azacitidine; ATRA Myelodysplastic syndromes; leukemia 
Romidepsin Depsipeptide I/II Bortezomib Multiple myeloma 
  II Bortezomib Multiple myeloma 
Belinostat PXD101 Azacitidine Leukemia; myelodysplastic syndromes 
  Bortezomib Advanced solid tumors, lymphomas 
MGCD0103  II Azacitidine Myelodysplastic syndrome; AML 
HDACiSynonymPhaseCombination drug(s)Indication
Vorinostat SAHA Azacitidine Nasopharyngeal carcinoma, lymphoma 
  Decitabine Advanced solid tumors, lymphoma, leukemia 
  Decitabine Hematologic cancer or other diseases 
  Decitabine Myelodysplastic syndromes, AML 
  Bortezomib Lung cancer 
  Bortezomib Metastatic solid tumors 
  Bortezomib Advanced lung cancer 
  Bortezomib Advanced multiple myeloma 
  NPI-0052 Lung cancer, pancreatic cancer, melanoma, lymphoma 
  I/II Azacitidine Myelodysplastic syndromes, AML 
  II Bortezomib Recurrent glioblastoma multiforme 
  II Bortezomib Recurrent lymphoma 
  II Bortezomib Refractory multiple myeloma 
  III Bortezomib Multiple myeloma 
Entinostat MS-275 Azacitidine Leukemia; myelodysplastic syndromes 
  I/II Azacitidine Lung cancer 
  II Azacitidine Leukemia; myelodysplastic syndromes 
Panobinostat LBH589 Bortezomib Multiple myeloma 
  I/II Decitabine Myelodysplastic syndromes, AML 
Valproic acid Valproate Azacitidine Advanced cancers 
  Decitabine Leukemia; lymphoma 
  Decitabine Lymphoma 
  Decitabine Lung cancer 
  II Decitabine Myelodysplastic syndromes; leukemia 
  I/II Azacitidine; ATRA Myelodysplastic syndromes; leukemia 
  II Azacitidine; ATRA Myelodysplastic syndromes 
  II Azacitidine; ATRA Myelodysplastic syndromes; leukemia 
Romidepsin Depsipeptide I/II Bortezomib Multiple myeloma 
  II Bortezomib Multiple myeloma 
Belinostat PXD101 Azacitidine Leukemia; myelodysplastic syndromes 
  Bortezomib Advanced solid tumors, lymphomas 
MGCD0103  II Azacitidine Myelodysplastic syndrome; AML 

NOTE: Sources: http://clinicaltrials.gov, http://www.cancer.gov/clinicaltrials.

Abbreviation: SAHA, suberoylanilide hydroxamic acid.

Clinical trials using HDACi in combination with recombinant TRAIL or agonistic anti-TRAIL receptor antibodies such as mapatumumab (anti-TRAIL receptor 1) or lexatumumab, AMG655 and Apomab (anti-TRAIL receptor 2), or pro-survival Bcl-2 family inhibitors have not yet been reported. However, a multicenter, phase 1b study of AMG 655 in combination with vorinostat in patients with relapsed or refractory low grade lymphoma, mantle cell lymphoma, diffuse large cell lymphoma, and Hodgkin's disease has been initiated (78). Clinical trials using agents that activate the TRAIL pathway as monotherapies have been initiated with encouraging safety profiles obtained (58). Clinical trials using ABT-263 as a monotherapy have been initiated and thus far it seems that predicted side effects such as thrombocytopenia are manageable. Although not the aim of these initial trials, antitumor responses in some of the patients have been achieved (66, 67).

HDACi hold enormous promise for the treatment of hematological and solid tumors, especially when used in combination with other anticancer agents. Although there are numerous reports demonstrating that HDACi can augment the antitumor effects of a diverse range of cancer therapeutics in vitro, in many instances the molecular events that underpin the combined effects remain ill-defined. However, as our knowledge of the mechanisms of action of HDACi continues to expand, and as we begin to understand how tumors may be intrinsically resistant to HDACi or acquire resistance, rational combination strategies can be implemented. Evidence already exists that this is achievable, either by combining HDACi with agents that augment the molecular (i.e., epigenetic/transcriptional) activities of HDACi, or enhance the biological antitumor responses (i.e., apoptosis) that HDACi elicit. Integrating functional cell-based assays with preclinical testing using tractable mouse models of cancer in which mechanisms of action, therapeutic efficacy, and toxicity of any combination regimen using HDACi can be analyzed could provide important information about future clinical studies that could and should be initiated.

R. Johnstone, commercial research grant, Merck, Novartis, Pfizer; consultant, Progen.

Grant support: R.W. Johnstone is a Pfizer Australia Research Fellow and is supported by NHMRC Program Grant 251608, the Cancer Council Victoria, the Leukaemia Foundation of Australia, and the Australian Rotary Health Research Fund. M. Bots is supported by a Rubicon research grant from Netherlands Organisation for Scientific Research (NWO).

1
Hanahan D, Weinberg RA. The hallmarks of cancer.
Cell
2000
;
100
:
57
–70. PubMed doi:10.1016/S0092–8674(00)81683–9.
2
Jones PA, Baylin SB. The epigenomics of cancer.
Cell
2007
;
128
:
683
–92. PubMed doi:10.1016/j.cell.2007.01.029.
3
McCabe MT, Brandes JC, Vertino PM. Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 2009;15:3927–37.
4
Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future.
Nat Rev Drug Discov
2006
;
5
:
37
–50. PubMed doi:10.1038/nrd1930.
5
Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors.
Nat Rev Drug Discov
2006
;
5
:
769
–84. PubMed doi:10.1038/nrd2133.
6
Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res 2009;15:3958–69. PubMed.
7
Schrump DS. Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin Cancer Res. In press 2009;15:3947–51.
8
Rasheed WK, Johnstone RW, Prince HM. Histone deacetylase inhibitors in cancer therapy.
Expert Opin Investig Drugs
2007
;
16
:
659
–78. PubMed doi:10.1517/13543784.16.5.659.
9
Lee MJ, Kim YS, Kummar S, Giaccone G, Trepel JB. Histone deacetylase inhibitors in cancer therapy.
Curr Opin Oncol
2008
;
20
:
639
–49. PubMed doi:10.1097/CCO.0b013e3283127095.
10
Issa JP, Kantarjian HM. Targeting DNA Methylation. Clin Cancer Res. In press 2009;15:3938–46.
11
Esteller M. Epigenetics in cancer.
N Engl J Med
2008
;
358
:
1148
–59. PubMed doi:10.1056/NEJMra072067.
12
Herranz M, Esteller M. DNA methylation and histone modifications in patients with cancer: potential prognostic and therapeutic targets.
Methods Mol Biol
2007
;
361
:
25
–62. PubMed.
13
Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer.
Nat Genet
1999
;
21
:
103
–7. PubMed doi:10.1038/5047.
14
Yamashita K, Upadhyay S, Osada M, et al. Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma.
Cancer Cell
2002
;
2
:
485
–95. PubMed doi:10.1016/S1535–6108(02)00215–5.
15
Zhu WG, Lakshmanan RR, Beal MD, Otterson GA. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors.
Cancer Res
2001
;
61
:
1327
–33. PubMed.
16
Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G. Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid.
Leuk Res
2005
;
29
:
739
–48. PubMed doi:10.1016/j.leukres.2004.11.022.
17
Scott SA, Dong WF, Ichinohasama R, et al. 5-Aza-2'-deoxycytidine (decitabine) can relieve p21WAF1 repression in human acute myeloid leukemia by a mechanism involving release of histone deacetylase 1 (HDAC1) without requiring p21WAF1 promoter demethylation.
Leuk Res
2006
;
30
:
69
–76. PubMed doi:10.1016/j.leukres.2005.05.010.
18
Coombes MM, Briggs KL, Bone JR, Clayman GL, El-Naggar AK, Dent SY. Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation.
Oncogene
2003
;
22
:
8902
–11. PubMed doi:10.1038/sj.onc.1207050.
19
Ferrara FF, Fazi F, Bianchini A, et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia.
Cancer Res
2001
;
61
:
2
–7. PubMed.
20
Cote S, Rosenauer A, Bianchini A, et al. Response to histone deacetylase inhibition of novel PML/RARα mutants detected in retinoic acid-resistant APL cells.
Blood
2002
;
100
:
2586
–96. PubMed doi:10.1182/blood-2002–02–0614.
21
He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia.
J Clin Invest
2001
;
108
:
1321
–30. PubMed.
22
Minucci S, Horn V, Bhattacharyya N, et al. A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells.
Proc Natl Acad Sci U S A
1997
;
94
:
11295
–300. PubMed doi:10.1073/pnas.94.21.11295.
23
Warrell RP, Jr., He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase.
J Natl Cancer Inst
1998
;
90
:
1621
–5. PubMed doi:10.1093/jnci/90.21.1621.
24
Reynolds CP, Lemons RS. Retinoid therapy of childhood cancer.
Hematol Oncol Clin North Am
2001
;
15
:
867
–910. PubMed doi:10.1016/S0889–8588(05)70256–2.
25
Coffey DC, Kutko MC, Glick RD, et al. Histone deacetylase inhibitors and retinoic acids inhibit growth of human neuroblastoma in vitro.
Med Pediatr Oncol
2000
;
35
:
577
–81. PubMed doi:10.1002/1096–911X(20001201)35:6<577::AID-MPO18>3.0.CO;2–3.
26
Hahn CK, Ross KN, Warrington IM, et al. Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation.
Proc Natl Acad Sci U S A
2008
;
105
:
9751
–6. PubMed doi:10.1073/pnas.0710413105.
27
Coffey DC, Kutko MC, Glick RD, et al. The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid.
Cancer Res
2001
;
61
:
3591
–4. PubMed.
28
De los Santos M, Zambrano A, Sanchez-Pacheco A, Aranda A. Histone deacetylase inhibitors regulate retinoic acid receptor β expression in neuroblastoma cells by both transcriptional and posttranscriptional mechanisms.
Mol Endocrinol
2007
;
21
:
2416
–26. PubMed doi:10.1210/me.2007–0151.
29
Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target?
Cancer Cell
2003
;
4
:
13
–8. PubMed doi:10.1016/S1535–6108(03)00165-X.
30
Rodriguez-Gonzalez A, Lin T, Ikeda AK, Simms-Waldrip T, Fu C, Sakamoto KM. Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation.
Cancer Res
2008
;
68
:
2557
–60. PubMed doi:10.1158/0008–5472.CAN-07–5989.
31
Banerji L, Sattler M. Targeting mutated tyrosine kinases in the therapy of myeloid leukaemias.
Expert Opin Ther Targets
2004
;
8
:
221
–39. PubMed doi:10.1517/14728222.8.3.221.
32
Bali P, Pranpat M, Swaby R, et al. Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2.
Clin Cancer Res
2005
;
11
:
6382
–9. PubMed doi:10.1158/1078–0432.CCR-05–0344.
33
Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.
Cell
2003
;
115
:
727
–38. PubMed doi:10.1016/S0092–8674(03)00939–5.
34
George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3.
Blood
2005
;
105
:
1768
–76. PubMed doi:10.1182/blood-2004–09–3413.
35
Guo F, Sigua C, Bali P, et al. Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells.
Blood
2005
;
105
:
1246
–55. PubMed doi:10.1182/blood-2004–05–2041.
36
Rahmani M, Reese E, Dai Y, et al. Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change.
Mol Pharmacol
2005
;
67
:
1166
–76. PubMed doi:10.1124/mol.104.007831.
37
Rao R, Fiskus W, Yang Y, et al. HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells.
Blood
2008
;
112
:
1886
–93. PubMed doi:10.1182/blood-2008–03–143644.
38
Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571.
Blood
2003
;
102
:
3765
–74. PubMed doi:10.1182/blood-2003–03–0737.
39
Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors.
Clin Cancer Res
2004
;
10
:
3839
–52. PubMed doi:10.1158/1078–0432.CCR-03–0561.
40
Nawrocki ST, Carew JS, Pino MS, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells.
Cancer Res
2006
;
66
:
3773
–81. PubMed doi:10.1158/0008–5472.CAN-05–2961.
41
Miller CP, Ban K, Dujka ME, et al. NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells.
Blood
2007
;
110
:
267
–77. PubMed doi:10.1182/blood-2006–03–013128.
42
Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells.
Blood
2003
;
101
:
3236
–9. PubMed doi:10.1182/blood-2002–08–2675.
43
Yu C, Rahmani M, Almenara J, et al. Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells.
Cancer Res
2003
;
63
:
2118
–26. PubMed.
44
Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B.
Mol Cancer Ther
2003
;
2
:
971
–84. PubMed.
45
Furumai R, Matsuyama A, Kobashi N, et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases.
Cancer Res
2002
;
62
:
4916
–21. PubMed.
46
Dai Y, Chen S, Kramer LB, Funk VL, Dent P, Grant S. Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells.
Clin Cancer Res
2008
;
14
:
549
–58. PubMed doi:10.1158/1078–0432.CCR-07–1934.
47
Copland JA, Marlow LA, Williams SF, et al. Molecular diagnosis of a BRAF papillary thyroid carcinoma with multiple chromosome abnormalities and rare adrenal and hypothalamic metastases.
Thyroid
2006
;
16
:
1293
–302. PubMed doi:10.1089/thy.2006.16.1293.
48
Lindemann RK, Newbold A, Whitecross KF, et al. Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma.
Proc Natl Acad Sci U S A
2007
;
104
:
8071
–6. PubMed doi:10.1073/pnas.0702294104.
49
Newbold A, Lindemann RK, Cluse LA, Whitecross KF, Dear AE, Johnstone RW. Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin.
Mol Cancer Ther
2008
;
7
:
1066
–79. PubMed doi:10.1158/1535–7163.MCT-07–2256.
50
Insinga A, Monestiroli S, Ronzoni S, et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway.
Nat Med
2005
;
11
:
71
–6. PubMed doi:10.1038/nm1160.
51
Fantin VR, Loboda A, Paweletz CP, et al. Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma.
Cancer Res
2008
;
68
:
3785
–94. PubMed doi:10.1158/0008–5472.CAN-07–6091.
52
Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer.
Nat Rev Drug Discov
2002
;
1
:
287
–99. PubMed doi:10.1038/nrd772.
53
Nebbioso A, Clarke N, Voltz E, et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells.
Nat Med
2005
;
11
:
77
–84. PubMed doi:10.1038/nm1161.
54
Aron JL, Parthun MR, Marcucci G, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein.
Blood
2003
;
102
:
652
–8. PubMed doi:10.1182/blood-2002–12–3794.
55
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications.
Proc Natl Acad Sci U S A
2004
;
101
:
540
–5. PubMed doi:10.1073/pnas.2536759100.
56
Bhalla KN. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.
J Clin Oncol
2005
;
23
:
3971
–93. PubMed doi:10.1200/JCO.2005.16.600.
57
Henderson C, Brancolini C. Apoptotic pathways activated by histone deacetylase inhibitors: implications for the drug-resistant phenotype.
Drug Resist Updat
2003
;
6
:
247
–56. PubMed doi:10.1016/S1368–7646(03)00067–0.
58
Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy.
Nat Rev Cancer
2008
;
8
:
782
–98. PubMed doi:10.1038/nrc2465.
59
Earel JK Jr, VanOosten RL, Griffith TS. Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells.
Cancer Res
2006
;
66
:
499
–507. PubMed doi:10.1158/0008–5472.CAN-05–3017.
60
Frew AJ, Lindemann RK, Martin BP, et al. Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.
Proc Natl Acad Sci U S A
2008
;
105
:
11317
–22. PubMed doi:10.1073/pnas.0801868105.
61
Yip KW, Reed JC. Bcl-2 family proteins and cancer.
Oncogene
2008
;
27
:
6398
–406. PubMed doi:10.1038/onc.2008.307.
62
Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential.
Curr Opin Immunol
2007
;
19
:
488
–96. PubMed doi:10.1016/j.coi.2007.05.004.
63
Whitecross KF, Alsop AE, Cluse LA, et al. Defining the target specificity of ABT-737 and synergistic anti-tumor activities in combination with histone deacetylase inhibitors.
Blood
2009
;
113
:
1982
–91.
64
Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.
Cancer Res
2008
;
68
:
3421
–8. PubMed doi:10.1158/0008–5472.CAN-07–5836.
65
Park CM, Bruncko M, Adickes J, et al. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
J Med Chem
2008
;
51
:
6902
–15. PubMed doi:10.1021/jm800669s.
66
Roberts A, Gandhi L, O'Connor OA, et al. Reduction in platelet counts as a mechanistic biomarker and guide for adaptive dose-escalation in phase I studies of the Bcl-2 family inhibitor ABT-263 [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
3542
.
67
Wilson WH, Czuczman MS, LaCasce AS, et al. A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of ABT-263 in subjects with refractory or relapsed lymphoid malignancies [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
8511
.
68
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia.
Blood
2006
;
108
:
3271
–9. PubMed doi:10.1182/blood-2006–03–009142.
69
Braiteh F, Soriano AO, Garcia-Manero G, et al. Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers.
Clin Cancer Res
2008
;
14
:
6296
–301. PubMed doi:10.1158/1078–0432.CCR-08–1247.
70
Garcia-Manero G, Yang AS, Klimek V, et al. Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) [abstract].
J Clin Oncol
2007
;
25
Suppl 18:
7062
.
71
Juergens RA, Vendetti F, Coleman B, et al. Phase I trial of 5-azacitidine (5AC) and SNDX-275 in advanced lung cancer (NSCLC) [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
19036
.
72
Karpenko MJ, Liu Z, Aimiuwu J, et al. Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in patients with NSCLC [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
3502
.
73
Odenike O, Green M, Larson RA, et al. Phase I study of belinostat (PXD101) plus azacitidine (AZC) in patients with advanced myeloid neoplasms [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
7057
.
74
Silverman LR, Verma A, Odchimar-Reissig R, et al. A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: A New York Cancer Consortium [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
7000
.
75
Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia.
J Clin Oncol
2007
;
25
:
3884
–91. PubMed doi:10.1200/JCO.2006.09.4169.
76
Badros AZ, Philip S, Niesvizk R, et al. Phase I trial of vorinostat plus bortezomib (bort) in relapsed/refractory multiple myeloma (mm) patients (pts) [abstract].
J Clin Oncol
2008
;
26
Suppl 15:
8548
.
77
Schelman WR, Kolesar J, Schell K, et al. A phase I study of vorinostat in combination with bortezomib in refractory solid tumors [abstract].
J Clin Oncol
2007
;
25
Suppl 18:
3573
.
78
cancer.gov [homepage on the Internet]. Bethesda (MD): National Cancer Institute, U.S. National Institutes of Health. Available from: http://www.cancer.gov.