Download Development of histone deacetylase inhibitors for cancer treatment

Review
Development of histone
deacetylase inhibitors for
cancer treatment
Douglas Marchion and Pamela Münster†
CONTENTS
HDAC enzymes & cancer
HDAC inhibitors
Biological effects of
HDAC inhibitors
Clinical experience
FDA-approved
HDAC inhibitors
Reported clinical
studies involving select
HDAC inhibitors
Other HDAC inhibitors in
clinical development
Rationally designed
combination of HDAC
inhibitors & other therapies
Potential targets
& future directions
Expert commentary
Five-year view
References
Affiliations
†
Author for correspondence
H Lee Moffitt Cancer Center,
Experimental Therapeutics and
Breast Medical Oncology Programs,
Department of Interdisciplinary
Oncology, 12902 Magnolia Dr.,
Tampa, FL 33612, USA
Tel.: +1 813 745 6893
Fax: +1 813 745 1984
[email protected]
KEYWORDS:
depsipeptide, HDAC, HDAC
inhibitor, LBH589,
MGCD0103, MS-275, PXD101,
sodium butyrate, valproic acid,
vorinostat, zolinza
www.future-drugs.com
Histone deacetylase (HDAC) inhibitors are an exciting new addition to the arsenal of
cancer therapeutics. The inhibition of HDAC enzymes by HDAC inhibitors shifts the balance
between the deacetylation activity of HDAC enzymes and the acetylation activity of
histone acetyltransferases, resulting in hyperacetylation of core histones. Exposure of
cancer cells to HDAC inhibitors has been associated with a multitude of molecular and
biological effects, ranging from transcriptional control, chromatin plasticity, protein–DNA
interaction to cellular differentiation, growth arrest and apoptosis. In addition to the
antitumor effects seen with HDAC inhibitors alone, these compounds may also potentiate
cytotoxic agents or synergize with other targeted anticancer agents. The exact
mechanism by which HDAC inhibitors cause cell death is still unclear and the specific roles
of individual HDAC enzymes as therapeutic targets has not been established. However,
emerging evidence suggests that the effects of HDAC inhibitors on tumor cells may not
only depend on the specificity and selectivity of the HDAC inhibitor, but also on the
expression patterns of HDAC enzymes in the tumor tissue. In this review, the recent
advances in the understanding and clinical development of HDAC inhibitors, as well as
their current role in cancer therapy, will be discussed.
Expert Rev. Anticancer Ther. 7(4), 583–598 (2007)
Aberrant gene transcription is a hallmark of cancer and anomalies in the regulation of transcription may lead to cellular transformation [1,2].
Transcriptional regulation is accomplished by a
complex interaction of several mechanisms
including histone tail modifications [3,4], DNA
methylation [5–7] and the activity of regulatory
proteins that interact with both histones and
DNA [8]. The first level of control over gene
activity is the addition or removal of chemical
groups to histone tail moieties, such as acetyl
groups [1].
The acetylation and deacetylation of histone
tails is accomplished by the competing activity
of histone acetyl transferases (HAT) and histone
deacetylases (HDACs), respectively [4]. Generally speaking, histone acetylation by HATs
masks the positive charges of lysine residues on
histone tails, thereby reducing the tight interaction between the histones and the negatively
charged DNA. In contrast, HDACs remove the
acetyl groups from the lysine residues of histone
10.1586/14737140.7.4.583
tails, reinstating the positive charge and subsequent interaction with the negatively charged
DNA [3,4]. In this respect, the acetylation status
of histones may determine the access of transcription factors to targets on the DNA promoters. Deregulation in the expression or activity of HATs and notably HDACs may lead to
alterations in gene expression profiles and has
been linked to the development of cancers [9,10].
HDAC enzymes & cancer
Several recent studies have implicated individual HDAC enzymes in the development of
cancer and as potential therapeutic targets.
HDACs can be divided into at least three different classes, I–III. Each class contains several
structurally and functionally variable HDACs
(TABLE 1) [11,12]. Class I HDAC enzymes include
HDAC 1–3 and 8 and are typically localized
to the nucleus. Class II HDAC enzymes
include HDAC 4–7, 9 and 10, and may exist
in both the nucleus and the cytoplasm. In
© 2007 Future Drugs Ltd
ISSN 1473-7140
583
Marchion & Münster
addition, HDAC11, which shows similarities to both class I
and II HDACs, is distinctive enough to be categorized by some
into a class IV [13]. Class III HDAC enzymes comprise nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases
termed sirtuins. The clinical relevance of sirtuins and their corresponding inhibitors remains unknown. A more in-depth
understanding of their preclinical roles may be derived from
recent reviews by the groups of Longo, Denu and Buck [14–16].
Currently, there are at least 17 known HDAC enzyme family
members. Given their global effect on histone modulation, it is
not surprising that the HDAC enzymes are involved in many
biological functions, ranging from transcriptional control,
chromatin plasticity and protein–DNA interaction to cellular
differentiation (FIGURE 1). An extensive body of literature proposes many relevant downstream effects involved in cell biology
and, in particular, in the development and proliferation of
tumors, and has been reviewed extensively [17–23].
A link between HDAC1 and HDAC3 expression with specific tumor features has been evaluated in breast cancer
tumor samples by several investigators. HDAC1 mRNA levels by real-time (RT)-PCR, as well as HDAC1 and HDAC3
protein expression by immunohistochemistry, were statistically associated with smaller, estrogen- and progesterone-positive tumors, while HDAC1 mRNA, but not HDAC1 protein expression was linked to node-negative tumors [24,25]. In
addition, increased HDAC1 mRNA and protein expression
were linked to better outcome, while HDAC3 expression did
not appear to impact overall or disease-free survival [24,25].
However, the reports were equivocal as to whether HDAC1
mRNA was an independent prognostic indicator or linked to
other features [24]. HDAC1 protein overexpression has also
been reported in gastric cancer; however, its role as a predictor has not been assessed [26]. In patients with esophageal
cancer, low HDAC1 expression was associated with a more
invasive phenotype [27].
Table 1. Histone deacetylase enzymes.
Class I
Class II
Class III
Class IV
Members HDAC1
HDAC4
(Sirtuins)
HDAC11
HDAC2
HDAC5
Sir2
HDAC3
HDAC6
Sirtuin
homologs
HDAC8
HDAC7
HDAC9
HDAC10
Function Related to
Rpd3
protein
Location
Ubiquitously Tissue-restricted
expressed
patterns of
expression
HDAC: Histone deacetylase.
584
Similarity to the
yeast Hda1
protein
Related
to Rpd3
protein
Ubiquitously
expressed
A retrospective analysis of banked tumor tissues suggested
that increased expression of HDAC6 was associated with
improved disease-free and overall survival in patients with hormone-sensitive breast tumors treated with tamoxifen [28]. Furthermore, a direct interaction of HDAC1 and the estrogen
receptor (ER) may be involved in the response to antiestrogen
therapy [29].
Expression of HDAC5 and HDAC10 were associated with
poor prognosis in lung cancer [30]. HDAC2 overexpression has
been found in precancerous lesions and colon cancers associated with the adenomatosis polyposis coli (APC) tumor-suppressor gene, suggesting that HDAC inhibitors may not only
have an important role in the treatment, but also in the prevention of colon cancer in family members affected by an APC
gene mutation [31].
Specific under- and overexpression patterns of HDAC
enzymes have been shown in acute myeloblastic leukemia
(AML). These patterns have been further correlated with
response to therapy; however, these studies will require further validation in clinical trials [32] and many more studies on
the prognostic role of select HDAC enzymes in cancer are
currently ongoing.
These studies suggest that individual HDAC enzymes may
play a role in the development and progression of cancer.
However, while these studies point toward individual HDAC
enzymes as prognostic factors and potential selective therapeutic targets, most were small and retrospective, and require
further validation. Furthermore, little is known regarding
the relevance of specific HDAC-expression patterns as
therapeutic targets.
HDAC inhibitors
The association of HDAC enzymes and carcinogenesis has
increased interest in the use of HDAC inhibitors as antitumor
agents [33–36]. HDAC inhibitors have been shown to induce cellcycle arrest, growth inhibition, chromatin decondensation, differentiation and apoptosis in several cancer cell types [18,37–41]. An
example of mammary differentiation in MCF-7 cells is shown in
FIGURE 2. HDAC inhibitors are classified by structure and include
the short-chain fatty acids, valproic acid (VPA) and sodium
butyrate (NaB); the cyclic tetrapeptides, depsipeptide; the
hydroxamic acids, suberoylanilide hydroxamic acid (SAHA),
trichostatin A (TSA), LAQ824, LBH529 and PXD101; and the
benzamides, MS-275 (TABLE 2) [18]. Although these HDAC inhibitors differ in structure, potency and possibly HDAC enzyme
selectivity, they target primarily class I and II HDAC enzymes
and do not affect the activity of the class III sirtuins (TABLE 1)
[11,12]. The downstream effects of HDAC inhibition, which ultimately lead to growth inhibition and apoptosis in different
tumor types, are currently under review and it is becoming
increasingly clear that these effects may depend upon the HDAC
inhibitor as well as the cell type [23,42,43]. HDAC inhibitors may
affect the epigenetic regulation of chromatin by shifting the balance between HDAC and HAT enzyme activity, resulting in the
hyperacetylation of histones. While the mechanism of action of
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
HDAC inhibitors should favor chromatin
decondensation and a global increase in
gene transcription, only a small percentage
The HDACs and
of genes are affected [44,45] and it appears
The HDACs
and
transcriptional
control
that as many genes are transcriptionally
transcriptional control
Histone code
HDAC:protein
downregulated as are transcriptionally
HDAC–protein
Regulation of transcription factor access
interactions
interactions
Histone code of HDAC inhibition
upregulated [9,23,37,46].
Transcriptional consequences
Regulation of transcription factor access
Multiprotein
While the induction of gene expression
Kinetics of histone acetylation/deacetylation
Transcriptional consequences of HDAC inhibition
Multiprotein
HDAC–corepressor
Nonhistone (de)acetylation
by HDAC inhibitors seems to occur by a
Kinetics of histone acetylation/deacetylation
HDAC -corepressor
complexes
Long-range
repression
histone (de)acetylation
Noncommon mechanism, the HDAC inhibicomplexes
HDAC complexes
Long-range repression
tor-induced repression of gene expression
Heterochromatin
HDAC complexes
may occur through multiple pathways
Heterochromatin
employing several accessory proteins. For
Post-translational
Biological
Biological
consequences
consequences
example, a commonality between several
modifications
ofofHDAC
HDACinhibition
inhibition
HDAC inhibitors is the induced expresCell differentiation
Phosphorylation
Cell differentiation
sion of the cell-cycle regulator, p21 [47,48].
Cell-cycle
arrest
Dephosphorylation
Cell cycle arrest
Apoptosis
SUMOylation
Treatment of cancer cells with the HDAC
Apoptosis
Cytoskeletal
alterations
inhibitor SAHA resulted in the association
Cytoskeletal alterations
Angiogenesis
Angiogenesis
of the p21 promoter with acetylated histones and a decrease in association with
HDAC1-containing repressor complexes Figure 1. Biological functions of HDAC enzymes.
[47,49,50]. Similarly, TSA treatment of HDAC: Histone deacetylase; SUMO: Small ubiquitin modifier.
MCF-7 cells resulted in a reduced association of the p100 resulted in increased acetylation of p52 and subsequent
Sin3a–HDAC repressor complex from the luteinizing hormone sequestration and inhibition of p65 binding to the cyclin
receptor promoter and, when coupled with a demethylation D1 promoter.
agent, resulted in gene expression [51].
By contrast, the reduced expression of ERα in MCF-7 Biological effects of HDAC inhibitors
breast cancer cells in response to the HDAC inhibitor TSA Cell growth arrest, differentiation & apoptosis
may involve a member of the sirtuin family of deacetylases in HDAC inhibitors have antitumor activity against several cancer
combination with local promoter methylation [52]. However, cell types [56–69]. A common sequelae of HDAC inhibitor treatthe repression of cB1 expression in HT-29 colon cancer cells ment is upregulation of p21 and downregulation of cyclin D,
after treatment with the HDAC inhibitor NaB was dependent resulting in reduced cancer cell proliferation and cell-cycle arrest
upon the induction of p21 [53,54]. In a more complex scenario, [47,70,71]. In breast cancer cell lines, growth arrest was associated
TSA was shown to downregulate the expression of cyclin D1 with morphological changes characteristic of differentiation,
in mouse JB6 cells through the activation of p100 processing including the production of milk fat proteins and a decrease in
of p52 [55]. These data suggest that TSA-induced activation of the nuclear–cytoplasmic ratio (FIGURE 2) [40,72–74]. Furthermore,
A
B
C
Figure 2. Mammary differentiation in breast cancer (MCF)-7 cells. Suberoylanilide hydroxamic acid (SAHA)-induced differentiation of MCF-7 cells required
continuous presence of drug. Cells were grown on Lab Tek™ cover culture chambers in the presence of 5 µM SAHA for 48 h. The SAHA-containing media was then
removed and the cells were cultured for an additional 48 h in complete media without drug. Cells were evaluated for the production of milk fat globulin (green) and
milk fat globule membrane protein (red). Nuclear DNA was stained with bisbenzimide. (A) 0 h, (B) 48 h of SAHA treatment, (C) 48 h after the removal of SAHA.
Images were acquired by confocal microscopy.
www.future-drugs.com
585
Marchion & Münster
HDAC inhibitor treatment may also induce apoptosis through
both the intrinsic and extrinsic pathways. HDAC inhibitors
have been shown to upregulate the expression of the proapoptotic proteins Bax, Bak, Bim, Bad, Noxa, Puma, Bid and
Apaf1 [75–84]; facilitate the translocation of Bax to the mitochondria [75,85]; and decrease the expression of the antiapoptotic proteins Bcl-2, Bcl-xl, Mcl-1 and survivin [86–89]. In addition, HDAC inhibitors have been shown to upregulate the
expression of Fas and tumor necrosis factor (TNF)-related
apoptosis-inducing ligand (TRAIL) receptors [90,91].
with the downregulation of structural maintenance of chromatin
(SMC) proteins 1–5, SMC-associated proteins, HCAP-H and
HCAP-G, DNA methyltransferase (DNMT)1 and heterochromatin protein (HP)1 (FIGURE 3) [39]. SMC proteins [92,93], DNMT1
[5–7] and HP1 [8,94,95] play specific roles in the condensation of
chromatin and are required for the proper formation of heterochromatin. These findings suggest that not only the HDAC inhibitor-induced hyperacetylation of histones but rather the downstream effects of HDAC inhibition leading to changes in gene
expression are required for the onset of chromatin decondensation.
Chromatin structure
Angiogenesis
HDAC inhibitors compete for the active site within HDAC
enzymes leading to the accumulation of acetyl groups on histone
tails [18]. This negates the charge interaction between histones and
the DNA, resulting in a loosened chromatin structure [3,4]. While
histone acetylation has been thought to be solely indicative of
chromatin decondensation, more recent data suggest a correlation
between HDAC inhibitor-induced modulation of gene expression
and HDAC inhibitor-induced chromatin decondensation [39].
While hyperacetylation of core histone is a rapid process induced
by HDAC inhibitors, structural changes to the chromatin required
prolonged exposure times to the HDAC inhibitors and correlated
An important aspect in tumor progression is the formation of
blood vessels or angiogenesis. Angiogenesis is an inducible
response, which may be triggered by hypoxia and serum starvation and is characterized by the expression of hypoxia-inducible
factor (HIF)1α and vascular endothelial growth factor
(VEGF) [96,97]. The HDAC inhibitors TSA [98–100], SAHA [99],
MS-275 [100], FK228 [101], phenylbutyrate [102], LBH589 [103]
and LAQ824 [104] have been shown to inhibit angiogenesis.
The mechanism by which this occurs seems to be through the
ability of HDAC inhibitors to modulate gene expression,
resulting in the repression of the proangiogenic factors such as
HIF1α, VEGF, VEGF receptor and
endothelial nitric oxide synthase and the
cytokines IL-2 and IL-8 [98,100,101,105–107]
and the induction of antiangiogenic factors, such as p53 and von Hippel–Lindau
(VHL) [98]. The clinical applicability of
these findings remains to be tested.
A
Immunity/inflammation
Relative mRNA expression
There is significant evidence suggesting
that HDAC inhibitors may modulate
inflammation and innate immune system
responses [108,109]. However, many reports
are in conflict as to whether HDAC
0h
inhibitors may suppress or enhance these
120
48 h
responses. In animal models, HDAC
B
100
inhibitors, such as TSA and SAHA, may
reduce graft-versus-host disease in experi80
mental bone marrow transplantation and
60
reduce symptoms of adjuvant-induced
rheumatoid arthritis and multiple sclero40
sis [110–112], presumably through a sup20
pression
of
the
proinflammatory
0
cytokines, including IL-12, TNFα, interSMC1 SMC2 SMC3 SMC4 SMC5 HCAP-HHCAP-G DNMT1 HP1
feron (IFN)γ and IL-23 [113–116]. In addition, the HDAC inhibitor LAQ824 was
Figure 3. Histone deacetylase inhibitor-induced chromatin decondensation. (A) Electron
micrographs showing chromatin dispersion in MCF-7 cells after a 48-h treatment with valproic acid 2 mM reported to reduce the migration of antigen-presenting cells as well as the activacompared with treatment with saline (vehicle; x32,000). (B) Microarray analysis showing a decrease in
heterochromatin maintenance protein mRNA expression in MCF-7 cells after a 48-h treatment with VPA
tion and chemotaxis of the T-helper
2 mM. Reduced expression of SMC protein 1-5, SMC-associated proteins, HCAP-H and HCAP-G, DNMT-1 (Th)1 subset of CD4+ T cells [113]. By
and HP-1 correlate with the onset of chromatin dispersion as shown in (A).
contrast, other groups have reported that
DNMT: DNA methyltransferase; HP: Heterochromatin protein; SMC: Structural maintenance of chromatin.
it is the activity of HDAC enzymes that
586
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
suppresses the expression of inflammatory genes [117] and
HDAC inhibitors may actually increase the cellular response to
the proinflammatory cytokine IL-6 [118]. However, it was suggested that these apparent contradictions may be due to the timing of HDAC inhibitor treatment [116]. TSA and SAHA were
shown to enhance lipopolysaccharide (LPS)-induced IL-6 secretion and inflammation in mouse and rat microglial cells when
given after LPS stimulation; however, anti-inflammatory effects
were noted when given prior to LPS stimulation [116]. These
findings are currently being evaluated in clinical studies.
Nonhistone targets
It has been suggested that the primary target of HATs and
HDACs may not be histones but nonhistone proteins [34] and
that acetylation may rival phosphorylation in substrate availability and substrate diversity [119,120]. Acetylation may affect the
activity and stability of proteins, as well as the ability of proteins to interact with DNA and other proteins [120]. An example
of this is signal transducer and activator of transcription
(STAT)3 where acetylation may direct STAT3 dimerization
and cellular localization [121,122]. Acetylation may also affect the
activity of E2F, p53, STAT1, c-Jun and many others [123–129].
The sheer number of transcription factors known to be
acetylated suggests that the acetylation of these nonhistone
proteins may have as much regulatory effect on transcription
as the acetylation of histone proteins. A more comprehensive
description of nonhistone targets of acetylation has been
reviewed recently [34,120,130].
Combinations of HDAC inhibitors & chemotherapy
Although HDAC inhibitors have shown antitumor activity
as single agents, promising interactions between HDAC
inhibitors and cytotoxic agents have been described in select
cancer cell types for platinum salts [131,132], taxanes [133,134],
topoisomerase inhibitors [38,39,56,67,135–138] and nucleoside
analogs [133,139,140]. HDAC inhibitors may further enhance
the activity of proteosome inhibitors [141–144], retinoic
acid [145–149], methylation inhibitors [150–153] or radiation
therapy [154–157]. However, the mechanisms by which HDAC
inhibitors potentiate these treatment modalities in specific
diseases are largely unknown with the exception of a subset of
acute promyelocytic leukemia (APL). Promyelocytic leukemia
(PML) is characterized by the expression of the PML–retinoic
acid receptor (RAR)α and the PML zinc finger
(PLZF)–RARα fusion proteins [158–160]. Cells expressing the
PML–RARα fusion protein are sensitive to treatment with
retinoic acid, while cells expressing the PLZF–RARα fusion
protein are not sensitive to retinoic acid [161]. In cells expressing the PLZF–RARα fusion protein, it was suggested that
HDAC1 was recruited to repress the retinoic acid response
genes [162,163]. HDAC inhibitors were found to restore retinoic acid sensitivity by reversing the transcriptional repression
of HDAC1 [160,164,165]. In this situation, it was the direct
activity of HDAC inhibitors that proved beneficial to the
enhancement of a therapeutic agent.
www.future-drugs.com
Table 2. Histone deacetylase inhibitors.
Class
Drugs
Clinical
development
(manufacturer)
Short-chain
fatty acids
Butyrate/phenyl
butyrate
Valproic acid
Phase I
Phase I/II (approved
for seizures; Abbott
Laboratories)
Cyclic tetrapeptides Depsipeptide (FK228) Phase III (Gloucester
Pharmaceuticals, Inc.)
CHAPs
Hydroxamic acids
TSA
Vorinostat
(ZolinzaTM, SAHA)
LBH589/LAQ824
PXD101
Amides
MS-275
MGCD0103
CI-994
Phase III (approved;
Merck)
Phase I/II (Novartis
Corp.)
Phase I/II (CuraGen
Corp., TopoTarget USA,
Inc.)
Phase III (Bayer
Schering Pharma AG)
Phase II (Methylgene,
Inc.)
Phase II (Pfizer, Inc.)
CHAP: Cyclic hydroxamic acid-containing peptide; SAHA: Suberoylanilide
hydroxamic acid; TSA: Trichostatin A.
In addition, the indirect effects of HDAC inhibitors to
induce chromatin decondensation may be successfully
exploited by combining them with DNA-targeting agents. The
HDAC inhibitor-induced chromatin decondensation may
facilitate the access of DNA-targeting agents to their DNA substrate, thereby enhancing the ensuing DNA damage. The proposed mechanism and the kinetics of the HDAC inhibitorinduced chromatin decondensation suggest that the sequence
of drug administration may be relevant. This was studied by
several investigators. Johnson and coworkers reported an antagonistic effect when the HDAC inhibitor TSA was combined
with the topoisomerase II inhibitor etoposide in leukemia
cells [137], whereas the groups of Tsai and Kurz reported
increased sensitivity [56,67]. These diametrically opposing
reports may be explained by differences in the sequence of drug
administration used in these studies. In the first study, Johnson
and coworkers pre-exposed leukemia cells to the HDAC inhibitor for 0.5 h prior to the topoisomerase inhibitor, while Kurz
and coworkers used 24–72 h HDAC inhibitor pre-exposures.
The relevance of drug sequencing and timing was further
reported by Marchion and coworkers [38,135]. Prolonged preexposure (24–48 h) to an HDAC inhibitor sensitized breast
cancer cell lines to the cytotoxic effects of topoisomerase inhibitors. A potentiation of the topoisomerase inhibitor by a
HDAC inhibitor was not observed with shorter pre-exposure
times (4–12 h) or with the administration of the topoisomerase
587
Marchion & Münster
inhibitor before the HDAC inhibitor [38,39]. A similar observation was reported by Kim and coworkers using the HDAC
inhibitors, SAHA (vorinostat) and TSA, in combination with
the topoisomerase inhibitor etoposide [136].
A cooperative activity between HDAC inhibitors and
topoisomerase I inhibitors has been noted by a number of
investigators; however, a review of the reported data suggests
that the benefits of adding a HDAC inhibitor to a
topoisomerase I inhibitor may depend not only on the schedule
of drug administration but also on specific tumor characteristics
and the type of topoisomerase I inhibitor used [38,136–138].
Clinical experience
HDAC inhibitors have been evaluated for their clinical feasibilities in different settings. Given the wide-ranging biological functions of HDACs, their inhibitors may have roles in different stages
of cancer development, ranging from cancer prevention to treatment of metastatic disease. However, as with many other novel
compounds, the initial clinical testing of the activity of HDAC
inhibitors typically involves studies in patients who have advanced
solid tumors or hematological malignancies; many of these
patients will have treatment-refractory tumors associated with
extensive prior therapy exposure. Furthermore, the absence of a
clearly defined target or a predictive marker does not allow the
enrichment of a target population of patients who are more likely
to respond to therapy, with the exception of patients with cutaneous T-cell lymphoma (CTCL). Furthermore, while many of the
preclinical studies postulate a potential class or compound specificity of HDAC inhibitors in their actions, its relevance has yet to
be determined in the clinical setting. The following sections will
describe the current state of the clinical development of several
HDAC inhibitors, with the caveat that these reports will change
rapidly as the clinical trials with HDAC inhibitors mature.
FDA-approved HDAC inhibitors
At the time of this review only vorinostat (Zolinza™, Merck
Inc.) has been approved as a HDAC inhibitor for clinical use.
Vorinostat (400 mg, administered orally daily) has received
approval for the treatment of refractory CTCL. The main
adverse effects associated with vorinostat include fatigue, nausea, dehydration, diarrhea and thrombocytopenia. Other potentially linked adverse effects include thromboembolic events.
However, as these events are not uncommon in cancer patients,
their relevance may be difficult to elucidate. In Phase II studies
in patients with CTLC or peripheral T-cell lymphoma (PTCL),
vorinostat resulted in an objective antitumor response in eight
of 33 patients and 14 patients had an improvement in their
symptoms [166]. Currently, vorinostat is being further evaluated
in this disease and in other hematological malignancies.
Reported clinical studies involving select HDAC inhibitors
Vorinostat (Zolinza)
In the first clinical trial, vorinostat (previously studied under
the name, SAHA) was initially administered intravenously for
3 days every 3 weeks and dose escalated to 5 days per week for
588
21 days. Out of 37 patients, four had an objective response;
two of these patients had lymphomas and two had bladder
cancer [167]. While the responses were encouraging, the number of
intravenous injections required in this regimen prompted a
change in formulation. Furthermore, emerging in vitro and
in vivo studies suggested a greater benefit of more continuous
rather than intermittent exposure to this HDAC inhibitor [40,168].
A subsequent Phase I trial with an oral formulation of vorinostat
in 73 patients showed responses in six patients, occurring at doses
of 400 mg twice daily or 600 mg once daily. Tumor histologies of
responding patients included lymphoma, laryngeal cancer, papillary thyroid cancer and mesotheliomas [169]. In particular, the
number of responses in patients with lymphomas seen in these
two Phase I trials suggested a potential role of vorinostat in this
disease [170]. Acetylation of histones induced by vorinostat was
seen in peripheral blood mononuclear cells as well as in tumor
cells. The observed histone acetylation persisted beyond the
pharmacological half-life of the drug [167].
Based on these findings, there are at least 37 ongoing clinical
trials for solid tumors as well as hematological malignancies
including leukemias and lymphomas, head and neck, prostate,
breast, kidney, thyroid and lung cancer, as well sarcomas,
melanomas and primary brain cancer. Vorinostat is being evaluated alone and in combination with targeted therapies or
chemotherapeutic agents [301].
Depsipeptide
The clinical development of depsipeptide included Phase I and II
trials in solid tumor malignancies as well as a Phase II trial in
patients with CTCL. In the initial Phase I trial evaluating depsipeptide as an intravenous infusion on days 1 and 5 every 21 days,
this compound was associated with nausea, vomiting, fatigue,
thrombocytopenia and cardiac arrhythmias manifesting as changes
in the electrocardiogram (ECG), as well as a case of atrial
fibrillation [171]. Histone acetylation was seen in peripheral blood
mononuclear cells [171]. Of 37 patients, one had an objective
response [171]. A second Phase I trial performed in the USA evaluated a weekly administration (3 out of 4 weeks) of depsipeptide in
33 patients with advanced cancer. Similar to the findings from the
Canadian study [171], ECG changes were also reported in this trial [172].
A Phase II trial in patients with CTCL and PTCL demonstrated further efficacy in this disease. Given as a weekly infusion
for 3 out of 4 weeks, antitumor activity was noted with depsipeptide in 10 of 27 patients with PTCL [173]. As seen in the Phase I
trials, the adverse effects associated with this drug included
fatigue, nausea and vomiting, as well as myelosuppression. This
trial showed no adverse effects on cardiac ejection fractions; however, there were further reports of conduction abnormalities, in
particular prolongation of the QTc-interval [173]. In solid tumors,
a Phase II trial in 29 patients with refractory renal cell cancer
showed an objective response rate in 7% of the patients [174] and
minimal activity in patients with neuroendocrine tumors [175].
Both of these trials were associated with QT prolongation, tachycardia and atrial fibrillation. Adverse cardiac effects were not
only seen in the adult population but also in children enrolled
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
in a trial for pediatric tumors [176]. While this drug may have
activity in hematological malignancies, the clinical relevance of
the adverse cardiac effects reported in several trials may have to
be carefully considered for its relationship to dose, formulation
or particular patient population. Currently, depsipeptide is
being evaluated in more than ten studies, either alone or in
combination [301].
an oral formulation afforded some clinical benefits. Toxicities
were similar to those seen with other HDAC inhibitors, however
there were no reported cardiac toxicities [187]. Unlike other
HDAC inhibitors, the half-life of this compound was found to
be fairly long (39–80 h), rendering daily dosing too toxic. While
a once-a-fortnight dosing at 10mg/m2 was feasible, histone
acetylation could not be maintained with this schedule. A weekly
dosing of this compound is currently being evaluated.
Valproic acid
VPA is currently marketed as an antiseizure drug and has been
available for over 30 years. Over the last few years, VPA has also
been used as a mood stabilizer and to treat migraine headaches.
Therapeutic doses typically range from 15 to 60 mg/kg/day
resulting in plasma concentrations of 30–130 µg/ml
(0.2–0.9 mM). It has recently being found to act as a HDAC
inhibitor [177–181]. Concentrations necessary for histone acetylation range from 0.25 to 5 mM. While VPA may not be a potent
HDAC inhibitor, concentrations required for in vitro efficacy are
achievable in patients. VPA has been evaluated as a HDAC
inhibitor in patients with leukemia either as a single agent or in
combination with all-trans retinoic acid (ATRA) in two clinical
trials. While VPA was well tolerated, the response rate for AML
was less than 10% [146,148]. By contrast, when VPA was combined with the demethylating agent 5-aza-2´deoxycitabine [182]
in 54 patients with refractory leukemia, the response rate was
22%, with a significant number of patients achieving complete
remission [183]. The maximally tolerated dose for VPA was
50 mg/kg/day administered daily for 10 days. The main toxicities were transient confusion and somnolence. Histone acetylation was evaluated in peripheral blood mononuclear cells and
tumor cells. While VPA-induced histone acetylation was noted
in only a few patients treated with the lower dose of VPA (20 and
35 mg/kg/day), histone acetylation was more commonly seen in
patients treated with higher doses of VPA (50 mg/kg/day). However, this trial did not suggest a correlation between histone
acetylation and response [183].
LBH589 & LAQ824
These two HDAC inhibitors of the hydroxamic class were found
to be highly potent and showed both in vitro and in vivo antitumor activity [184–186]. A Phase I trial involving 15 patients with
acute leukemia and myelodysplastic syndrome (MDS) evaluated
an intravenous infusion of LBH589. While this trial did not
report objective responses, toxicities were similar to those
reported with other HDAC inhibitors with regards to nausea,
vomiting, fatigue and thrombocytopenia. In addition, the intravenous administration of this drug was associated with QTc prolongations. Further studies with an oral formulation of LBH589,
either alone or in combination, are currently underway.
Other HDAC inhibitors in clinical development
MS-275
MS-275 was initially studied as an intravenous formulation;
however, a recently reported Phase I trial in patients with
advanced solid tumor malignancies or lymphomas suggested that
www.future-drugs.com
MGCD0103
MGCD0103, a class I-specific HDAC inhibitor, has passed
Phase I trials and is currently in Phase II trials either alone or
in combination with the demethylating agent, 2´-deoxy-5-azacytidine (Vidaza®), for AML and MDS. In addition, Phase II
monotherapy trials have been initiated for refractory Hodgkin’s lymphoma and B-cell lymphoma, as well as trials evaluating MGCD0103 in combination with gemcitabine. The
outcomes of these trials have not yet been published [301].
Sodium butyrate
Sodium butyrate, a HDAC inhibitor of the fatty acid group,
was studied in an oral formulation. Toxicities were similar to
other HDAC inhibitors, including fatigue, nausea and vomiting. However, no objective responses were seen with this
compound [188]. No trials are currently listed evaluating this
compound for patients with cancer [301].
PXD101
PXD101 is a novel hydroxamate-type HDAC inhibitor that
exhibits in vitro cytotoxicity at low micromolar concentrations [189].
Based on preclinical data suggesting single-agent efficacy of this
agent in ovarian cancer and a synergistic interaction with carboplatin or a taxane [190], several clinical trials were initiated and
are currently ongoing. Areas of interest in these trials include
the use of PXD101 in patients with CTCL, non-Hodgkin’s
lymphoma, AML and MDS either alone or in combination
with 2´-deoxy-5-azacytidine, bortezomib, isotretinoin or
17-N-allylamino-17-demethoxygeldanamycin. Clinical trials
for patients with solid tumors are focused on ovarian and liver
cancer, mesotheliomas and sarcomas [301].
Rationally designed combination of HDAC inhibitors
& other therapies
Several investigators have focused on the preclinical and
clinical development of HDAC inhibitors in combination
with other targeted therapies or cytotoxic agents. Our group
has mainly focused on HDAC inhibitors in combination
with DNA-targeting agents. In vitro and in vivo studies suggested that pre-exposure of cells to an HDAC inhibitor
resulted in chromatin decondensation, thus facilitating the
interaction between the DNA-targeting agents and their
DNA substrate and topoisomerase II target recruitment. This
was associated with an increase in the topoisomerase inhibitor-induced DNA damage and cell death. While these findings were not limited to a certain class of HDAC inhibitor,
589
Marchion & Münster
the preclinical in vivo efficacy and the well-established clinical toxicity profile had rendered VPA an ideal candidate for a
combination study. In particular, the absence of any known
cardiac toxicity (as initially suspected with depsipeptide) was
crucial for the combination with an anthracycline. Based on
extensive preclinical studies suggesting a synergistic interaction, the efficacy of a sequence-specific administration of
VPA followed by the topoisomerase II inhibitor epirubicin
was evaluated. A total of 44 patients with advanced solid
tumor malignancies were treated with increasing doses of
VPA for 3 days and epirubicin on day 3, cycles were repeated
every 3 weeks. Beginning at doses typically administered for
seizure disorders, the VPA doses were escalated to maximally
tolerated doses of 140 mg/kg/day VPA. The dose-limiting
toxicities of this combination were transient neurovestibular
(somnolence, dizziness, confusion) associated with VPA and
neutropenia associated predominantly with epirubicin. An
exacerbation of the epirubicin-induced myelosuppression or
cardiac toxicity was not observed. As seen with other VPA trials, the neurotoxicities were exacerbated by other neurotropic
agents [183]. Despite a median of three prior regimens and
prior anthracycline exposure in 25% of the patients, objective
responses were seen in 22% patients and 39% of patients had
a clinical benefit for at least 12 weeks. This combination is
currently being explored in a Phase II trial as primary therapy
in women with locally advanced breast cancer [191].
Other studies exploring HDAC inhibitors in combination
with DNA-damaging agents include a Phase I/II trial of VPA
and the topoisomerase I inhibitor karenitecin in advanced
melanoma, a combination of vorinostat and doxorubicin in
solid tumors and a combination of VPA and temozolomide
in patients with brain metastasis undergoing whole-brain
radiation therapy.
Potential targets & future directions
The treatment of cancer cells with HDAC inhibitors may
result in cell-cycle arrest, growth inhibition, differentiation,
chromatin decondensation and apoptosis. However, these
effects may vary with dose and between HDAC inhibitors, cell
type and even cell line. For example, treatment of MCF-7
breast cancer cells with 0.5 µM SAHA resulted in histone
acetylation within 1 h of exposure and chromatin decondensation after 48 h of exposure [38]. In contrast, at concentrations
five- and tenfold higher, treatment of MCF-7 cells with SAHA
resulted in a cell-cycle arrest in G1 and G2/M, respectively [40].
In addition, treatment of MCF-7 cells with VPA resulted in
G1 cell-cycle arrest at concentrations above 3 mM; however,
cell-cycle arrest in G2 was not achieved even with VPA doses
that exceeded 5 mM (MUNSTER, UNPUB. DATA). These observations suggest that the various biological effects observed in
response to HDAC inhibitors may be mediated through the
inhibition of different HDAC enzymes. Similarly, varying
effects of HDAC inhibitors the on cell cycle have been
reported with other HDAC inhibitors [138]. Therefore, the
questions become:
590
• Which HDAC enzyme is important in each of the observed
biological consequences of HDAC inhibitors?
• Does more than one HDAC enzyme, or inhibition thereof,
contribute to an individual effect?
• Are HDAC enzymes redundant in function?
The answers to these questions are dependent on the elucidation of the biological function of individual HDAC enzymes. It
is well documented that HDAC1 and HDAC2 coexist in several
multiprotein, corepressor complexes, such as NuRD, Sin3 and
CoREST [192–196]. Although this may suggest that these enzymes
may have redundancy, several reports indicate that HDAC
enzymes have individual functions and are differentially regulated [46,197,198]. HDAC1 has been associated with proliferation
in several tumor cell types, as well as differentiation in MCF-7
breast cancer cells and zebrafish retina [74,199–201], whereas
HDAC2 may be associated with cell survival [31,202] but may also
be involved in differentiation of endometrial stromal sarcoma
cells [203]. HDAC3 may be involved in colon cell maturation [204]
and may be required for the activity of HDAC 4, 5 and
7 [205,206]. HDAC4 may be involved in bone development [207]
and may play a role in muscle differentiation in conjunction with
HDAC5 and 7 [208–210]. HDAC6 may play a role in the regulation of the cytoskeleton [211–213], whereas HDAC7 may also be
involved in maintaining vascular integrity [214], while HDAC8
was reportedly associated with smooth muscle cell differentiation
and contractility [215,216]. The biological function of the remaining class I and II HDAC enzymes remains largely unknown.
These studies elucidating the biological function and regulation
of HDAC enzymes are imperative as they may not only answer
the previous questions, but may guide the future development of
HDAC inhibitors. Currently, most of the available HDAC inhibitors are nonspecific, targeting multiple class I and II HDAC
enzymes [217]. For example, TSA is a pan-histone inhibitor but
may have the highest potency toward HDAC1, 3 and 8, while
MS-275 may preferentially inhibit HDAC1 [218]. In addition,
VPA may have the highest activity against HDAC1 and 2, but
also affects HDAC3, 4, 5 and 7 in higher concentrations [179].
These findings suggest that different HDAC inhibitors may be
most effective in tumors that express the target enzymes of those
inhibitors. Furthermore, it is well known that not all cell types or
even cell lines within the same disease type, respond the same to
a particular HDAC inhibitor. This would, therefore, suggest that
HDAC enzyme expression may dictate sensitivity differentially
to various HDAC inhibitors. This idea is supported by Ropero
and coworkers study evaluating colorectal cell line sensitivity to
different HDAC inhibitors [219]. This study found that cells that
express mutated HDAC2 were resistant to histone acetylation
and cell-cycle arrest induced by the hydroxamic acid TSA but
not by the short-chain fatty acids butyrate or VPA.
Expert commentary
Several preclinical and clinical studies have indicated the value
of HDAC inhibitors as monotherapy and in combination with
either more standard chemotherapy or targeted therapy. The
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
first HDAC inhibitor has recently been approved for the treatment of CTCL. Many trials involving a number of different
HDAC inhibitors are currently ongoing, either as monotherapy
or in combination.
However, the mechanism(s) by which HDAC inhibitor treatment leads to these biological sequelae is not yet known and
may differ between the HDAC inhibitor used, and may ultimately depend on the differential expression patterns of HDAC
enzymes in tumors. Furthermore, the mode of action leading to
cell growth arrest and cell death may differ from those resulting
in potentiation of other antitumor therapies. As cellular markers that may predict response to HDAC inhibitors alone or in
combination with chemotherapy are not yet defined, the selection of patients remains arbitrary and may not include those
most likely to benefit from these agents. Further studies are
required to determine whether potency and/or class specificity
of the HDAC inhibitor are clinically relevant. To achieve the
optimal therapeutic potential of these novel and exciting compounds, HDAC inhibitors, it is imperative that future studies
focus on the biological roles of select HDAC enzymes and the
cellular consequences of the specific inhibition of individual
HDAC inhibitors.
Five-year view
The first HDAC inhibitor has been approved for use in
CTCL. Currently, it is not entirely clear why this compound
is active against this type of malignancy. Many other HDAC
inhibitors are currently being tested in this disease and appear
to be active. Further studies will show whether one representative within the same class or from a different class will be
superior to the currently approved vorinostat.
There is a suggestion of activity of HDAC inhibitors in other
malignancies; however, there are currently no markers to foretell response. The roles of individual HDAC enzymes in tumor
development or proliferation as well as therapeutic targets will
be essential for progression in the field.
References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1
2
3
4
Santos-Rosa H, Caldas C. Chromatin
modifier enzymes, the histone code and
cancer. Eur. J. Cancer 41(16), 2381–2402
(2005).
HDAC inhibitors are currently being evaluated in combination
with chemotherapy, antihormonal therapies or therapies targeting
specific pathways. The mechanism of synergy may differ from the
mechanism of action leading to cell death in CTCL. Different
HDAC enzymes may need to be inhibited. Furthermore, while
most of the currently used HDAC inhibitors are administered in
a more chronic form as single agents, this may need to be re-evaluated when combining HDAC inhibitors with other anticancer
agents. Higher doses at shorter intervals may be more applicable
when combining these agents with chemotherapy.
Key issues
• Histone deacetylase (HDAC) enzymes have been linked to the
development and progression of cancers.
• HDAC inhibitors have antitumor activity in certain cancer
types but may also act as sensitizers to chemotherapy.
• The sensitivity of cancer cells to HDAC inhibitors may depend
on the class of HDAC inhibitor, dose of administration and
the cell type.
• The biological effects of HDAC inhibition, such as cell-cycle
arrest and differentiation, may be mediated through
different HDAC enzymes.
• The first HDAC inhibitor (vorinostat) has been approved for
the treatment of cutaneous T-cell lymphoma.
For the optimal use of HDAC inhibitors as anticancer agents,
future experiments must:
• Define cellular markers that predict response to HDAC
inhibitors as monotherapy or as sensitizers to chemotherapy
in individual diseases.
• Determine whether selective versus nonselective HDAC
inhibitors are more efficacious.
• Determine whether high short-term doses or chronic
administration of lower doses are optimal.
5
Bird A. DNA methylation patterns and
epigenetic memory. Genes Dev. 16(1),
6–21 (2002).
6
Herman JG, Baylin SB. Gene silencing in
cancer in association with promoter
hypermethylation. N. Engl. J. Med.
349(21), 2042–2054 (2003).
7
Jones PA, Baylin SB. The fundamental
role of epigenetic events in cancer.
Nat. Rev. Genet. 3(6), 415–428 (2002).
Vogelstein B, Kinzler KW. Cancer genes
and the pathways they control. Nat. Med.
10(8), 789–799 (2004).
8
Allfrey VG, Faulkner R, Mirsky AE.
Acetylation and methylation of histones
and their possible role in the regulation of
RNA synthesis. Proc. Natl Acad. Sci. USA
51, 786–794 (1964).
Jones DO, Cowell IG, Singh PB.
Mammalian chromodomain proteins:
their role in genome organisation and
expression. Bioessays 22(2), 124–137
(2000).
9
Johnstone RW. Histone-deacetylase
inhibitors: novel drugs for the treatment of
cancer. Nat. Rev. Drug Discov. 1(4),
287–299 (2002).
Grunstein M. Histone acetylation in
chromatin structure and transcription.
Nature 389(6649), 349–352 (1997).
www.future-drugs.com
10
Taddei A, Roche D, Bickmore WA,
Almouzni G. The effects of histone
deacetylase inhibitors on heterochromatin:
implications for anticancer therapy?
EMBO Rep. 6(6), 520–524 (2005).
11
Yang WM, Tsai SC, Wen YD, Fejer G,
Seto E. Functional domains of histone
deacetylase-3. J. Biol. Chem. 277(11),
9447–9454 (2002).
12
Yang WM, Yao YL, Sun JM, Davie JR,
Seto E. Isolation and characterization of
cDNAs corresponding to an additional
member of the human histone deacetylase
gene family. J. Biol. Chem. 272(44),
28001–28007 (1997).
13
Gao L, Cueto MA, Asselbergs F, Atadja P.
Cloning and functional characterization of
HDAC11, a novel member of the human
histone deacetylase family. J. Biol. Chem.
277(28), 25748–25755 (2002).
591
Marchion & Münster
14
Longo VD, Kennedy BK. Sirtuins in aging
and age-related disease. Cell 126(2),
257–268 (2006).
15
Denu JM. The Sir 2 family of protein
deacetylases. Curr. Opin. Chem. Biol. 9(5),
431–440 (2005).
16
Buck SW, Gallo CM, Smith JS. Diversity in
the Sir2 family of protein deacetylases.
J. Leukoc. Biol. 75(6), 939–950
(2004).
17
Vigushin DM, Coombes RC. Histone
deacetylase inhibitors in cancer treatment.
Anticancer Drugs 13(1), 1–13 (2002).
18
Marks P, Rifkind RA, Richon VM et al.
Histone deacetylases and cancer: causes and
therapies. Nat. Rev. Cancer 1(3), 194–202
(2001).
19
Jung M. Inhibitors of histone deacetylase as
new anticancer agents. Curr. Med. Chem.
8(12), 1505–1511 (2001).
20
21
22
Kelly WK, O’Connor OA, Marks PA.
Histone deacetylase inhibitors: from target
to clinical trials. Expert Opin. Investig. Drugs
11(12), 1695–1713 (2002).
Arts J, de Schepper S, Van Emelen K.
Histone deacetylase inhibitors: from
chromatin remodeling to experimental
cancer therapeutics. Curr. Med. Chem.
10(22), 2343–2350 (2003).
Dokmanovic M, Marks PA. Prospects:
histone deacetylase inhibitors. J. Cell
Biochem. 96(2), 293–304 (2005).
24
Zhang Z, Yamashita H, Toyama T et al.
Quantitation of HDAC1 mRNA expression
in invasive carcinoma of the breast. Breast
Cancer Res. Treat. 94(1), 11–16 (2005).
26
30
31
32
Krusche CA, Wulfing P, Kersting C et al.
Histone deacetylase-1 and -3 protein
expression in human breast cancer: a tissue
microarray analysis. Breast Cancer Res. Treat.
90(1), 15–23 (2005).
Toh Y, Yamamoto M, Endo K et al. Histone
H4 acetylation and histone deacetylase 1
expression in esophageal squamous cell
carcinoma. Oncol. Rep. 10(2), 333–338
(2003).
28
Saji S, Kawakami M, Hayashi S et al.
Significance of HDAC6 regulation via
estrogen signaling for cell motility and
prognosis in estrogen receptor-positive
breast cancer. Oncogene 24(28), 4531–4539
(2005).
592
Osada H, Tatematsu Y, Saito H et al.
Reduced expression of class II histone
deacetylase genes is associated with poor
prognosis in lung cancer patients. Int. J.
Cancer 112(1), 26–32 (2004).
Zhu P, Martin E, Mengwasser J et al.
Induction of HDAC2 expression upon
loss of APC in colorectal tumorigenesis.
Cancer Cell 5(5), 455–463 (2004).
Bradbury CA, Khanim FL, Hayden R
et al. Histone deacetylases in acute
myeloid leukaemia show a distinctive
pattern of expression that changes
selectively in response to deacetylase
inhibitors. Leukemia 19(10), 1751–1759
(2005).
Bolden JE, Peart MJ, Johnstone RW.
Anticancer activities of histone deacetylase
inhibitors. Nat. Rev. Drug Discov. 5(9),
769–784 (2006).
34
Minucci S, Pelicci PG. Histone
deacetylase inhibitors and the promise of
epigenetic (and more) treatments for
cancer. Nat. Rev. Cancer 6(1), 38–51
(2006).
35
Rosato RR, Grant S. Histone deacetylase
inhibitors: insights into mechanisms of
lethality. Expert Opin. Ther. Targets 9(4),
809–824 (2005).
36
Caron C, Boyault C, Khochbin S.
Regulatory cross-talk between lysine
acetylation and ubiquitination: role in the
control of protein stability. Bioessays
27(4), 408–415 (2005).
37
Butler LM, Zhou X, Xu WS et al.
The histone deacetylase inhibitor SAHA
arrests cancer cell growth, up-regulates
thioredoxin-binding protein-2, and
down-regulates thioredoxin. Proc. Natl
Acad. Sci. USA 99(18), 11700–11705
(2002).
Choi JH, Kwon HJ, Yoon BI et al.
Expression profile of histone deacetylase 1
in gastric cancer tissues. Jpn. J. Cancer Res.
92(12), 1300–1304 (2001).
27
Varshochi R, Halim F, Sunters A et al.
ICI182,780 induces p21Waf1 gene
transcription through releasing histone
deacetylase 1 and estrogen receptor α
from Sp1 sites to induce cell cycle arrest in
MCF-7 breast cancer cell line. J. Biol.
Chem. 280(5), 3185–3196
(2005).
33
Sengupta N, Seto E. Regulation of histone
deacetylase activities. J. Cell. Biochem. 93(1),
57–67 (2004).
23
25
29
38
Marchion DC, Bicaku E, Daud AI et al.
Sequence-specific potentiation of
topoisomerase II inhibitors by the histone
deacetylase inhibitor suberoylanilide
hydroxamic acid. J. Cell Biochem. 92(2),
223–237 (2004).
39
Marchion DC, Bicaku E, Daud AI,
Sullivan DM, Munster PN. Valproic acid
alters chromatin structure by regulation of
chromatin modulation proteins. Cancer
Res. 65(9), 3815–3822 (2005).
40
Munster PN, Troso-Sandoval T, Rosen N
et al. The histone deacetylase inhibitor
suberoylanilide hydroxamic acid induces
differentiation of human breast cancer cells.
Cancer Res. 61(23), 8492–8497 (2001).
41
Secrist JP, Zhou X, Richon VM.
HDAC inhibitors for the treatment of
cancer. Curr. Opin. Investig. Drugs 4(12),
1422–1427 (2003).
42
Gray SG, Qian CN, Furge K, Guo X,
Teh BT. Microarray profiling of the effects of
histone deacetylase inhibitors on gene
expression in cancer cell lines. Int. J. Oncol.
24(4), 773–795 (2004).
43
Peart MJ, Smyth GK, van Laar RK et al.
Identification and functional significance of
genes regulated by structurally different
histone deacetylase inhibitors. Proc. Natl
Acad. Sci. USA 102(10), 3697–3702 (2005).
44
Della Ragione F, Criniti V, Della Pietra V
et al. Genes modulated by histone
acetylation as new effectors of butyrate
activity. FEBS Lett. 499(3), 199–204 (2001).
45
Van Lint C, Emiliani S, Verdin E.
The expression of a small fraction of cellular
genes is changed in response to histone
hyperacetylation. Gene Expr. 5(4–5),
245–253 (1996).
46
Marks PA, Richon VM, Miller T, Kelly WK.
Histone deacetylase inhibitors. Adv. Cancer
Res. 91, 137–168 (2004).
47
Richon VM, Sandhoff TW, Rifkind RA,
Marks PA. Histone deacetylase inhibitor
selectively induces p21WAF1 expression and
gene-associated histone acetylation. Proc.
Natl Acad. Sci. USA 97(18), 10014–10019
(2000).
48
Bhalla KN. Epigenetic and chromatin
modifiers as targeted therapy of hematologic
malignancies. J. Clin. Oncol. 23(17),
3971–3993 (2005).
49
Gui CY, Ngo L, Xu WS, Richon VM,
Marks PA. Histone deacetylase (HDAC)
inhibitor activation of p21WAF1 involves
changes in promoter-associated proteins,
including HDAC1. Proc. Natl Acad. Sci.
USA 101(5), 1241–1246 (2004).
50
Sambucetti LC, Fischer DD, Zabludoff S
et al. Histone deacetylase inhibition
selectively alters the activity and expression
of cell cycle proteins leading to specific
chromatin acetylation and antiproliferative
effects. J. Biol. Chem. 274(49),
34940–34947 (1999).
51
Zhang Y, Fatima N, Dufau ML.
Coordinated changes in DNA methylation
and histone modifications regulate
silencing/derepression of luteinizing
hormone receptor gene transcription.
Mol. Cell. Biol. 25(18), 7929–7939 (2005).
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
52
53
54
55
56
57
58
59
60
61
62
Reid G, Metivier R, Lin CY et al. Multiple
mechanisms induce transcriptional silencing
of a subset of genes, including oestrogen
receptor α, in response to deacetylase
inhibition by valproic acid and trichostatin
A. Oncogene 24(31), 4894–4907 (2005).
Archer SY, Meng S, Shei A, Hodin RA.
p21(WAF1) is required for butyratemediated growth inhibition of human colon
cancer cells. Proc. Natl Acad. Sci. USA
95(12), 6791–6796 (1998).
of peripheral and cutaneous T-cell
lymphoma: a case report. Blood 98(9),
2865–2868 (2001).
63
64
Planchon P, Magnien V, Beaupain R et al.
Differential effects of butyrate derivatives
on human breast cancer cells grown as
organotypic nodules in vitro and as
xenografts in vivo. In vivo 6(6), 605–610
(1992).
Rosato RR, Maggio SC, Almenara JA et al.
The histone deacetylase inhibitor LAQ824
induces human leukemia cell death through
a process involving XIAP down-regulation,
oxidative injury, and the acid
sphingomyelinase-dependent generation of
ceramide. Mol. Pharmacol. 69(1), 216–225
(2006).
Archer SY, Johnson J, Kim HJ et al.
The histone deacetylase inhibitor butyrate
downregulates cyclin B1 gene expression via
a p21/WAF-1-dependent mechanism in
human colon cancer cells. Am. J. Physiol.
Gastrointest. Liver Physiol. 289(4),
G696–G703 (2005).
65
Hu J, Colburn NH. Histone deacetylase
inhibition down-regulates cyclin D1
transcription by inhibiting nuclear factorκB/p65 DNA binding. Mol. Cancer Res.
3(2), 100–109 (2005).
Ryu JK, Lee WJ, Lee KH et al. SK-7041, a
new histone deacetylase inhibitor, induces
G2-M cell cycle arrest and apoptosis in
pancreatic cancer cell lines. Cancer Lett.
237(1), 143–154 (2006).
66
Takai N, Ueda T, Nishida M, Nasu K,
Narahara H. Anticancer activity of MS-275,
a novel histone deacetylase inhibitor, against
human endometrial cancer cells. Anticancer
Res. 26(2A), 939–945 (2006).
Kurz EU, Wilson SE, Leader KB et al.
The histone deacetylase inhibitor sodium
butyrate induces DNA topoisomerase II α
expression and confers hypersensitivity to
etoposide in human leukemic cell lines.
Mol. Cancer Ther. 1(2), 121–131
(2002).
Li GC, Zhang X, Pan TJ, Chen Z, Ye ZQ.
Histone deacetylase inhibitor trichostatin A
inhibits the growth of bladder cancer cells
through induction of p21WAF1 and G1 cell
cycle arrest. Int. J. Urol. 13(5), 581–586
(2006).
Marks PA, Michaeli J, Jackson J,
Richon VM, Rifkind RA. Induced
differentiation of murine erythroleukemia
cells (MELC) by polar compounds: marked
increased sensitivity of vincristine resistant
MELC. Prog. Clin. Biol. Res. 316B, 171–181
(1989).
Marks PA, Richon VM, Kiyokawa H,
Rifkind RA. Inducing differentiation of
transformed cells with hybrid polar
compounds: a cell cycle-dependent process.
Proc. Natl Acad. Sci. USA 91(22),
10251–10254 (1994).
Mukhopadhyay NK, Weisberg E,
Gilchrist D et al. Effectiveness of trichostatin
A as a potential candidate for anticancer
therapy in non-small-cell lung cancer. Ann.
Thorac. Surg. 81(3), 1034–1042 (2006).
Phillips A, Bullock T, Plant N. Sodium
valproate induces apoptosis in the rat
hepatoma cell line, FaO. Toxicology
192(2–3), 219–227 (2003).
Piekarz RL, Robey R, Sandor V et al.
Inhibitor of histone deacetylation,
depsipeptide (FR901228), in the treatment
www.future-drugs.com
67
Tsai SC, Valkov N, Yang WM et al.
Histone deacetylase interacts directly with
DNA topoisomerase II. Nat. Genet. 26(3),
349–353 (2000).
68
Weisberg E, Catley L, Kujawa J et al.
Histone deacetylase inhibitor
NVP-LAQ824 has significant activity
against myeloid leukemia cells in vitro and
in vivo. Leukemia 18(12), 1951–1963
(2004).
69
Wetzel M, Premkumar DR, Arnold B,
Pollack IF. Effect of trichostatin A, a
histone deacetylase inhibitor, on glioma
proliferation in vitro by inducing cell cycle
arrest and apoptosis. J. Neurosurg.
103(Suppl. 6), 549–556 (2005).
70
71
72
Vrana JA, Decker RH, Johnson CR et al.
Induction of apoptosis in U937 human
leukemia cells by suberoylanilide
hydroxamic acid (SAHA) proceeds through
pathways that are regulated by
Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but
independent of p53. Oncogene 18(50),
7016–7025 (1999).
Sandor V, Senderowicz A, Mertins S et al.
p21-dependent g(1) arrest with
downregulation of cyclin D1 and
upregulation of cyclin E by the histone
deacetylase inhibitor FR901228. Br. J.
Cancer 83(6), 817–825 (2000).
Abe M, Kufe DW. Sodium butyrate
induction of milk-related antigens in
human MCF-7 breast carcinoma cells.
Cancer Res. 44(10), 4574–4577 (1984).
73
Davis T, Kennedy C, Chiew YE, Clarke CL,
deFazio A. Histone deacetylase inhibitors
decrease proliferation and modulate cell cycle
gene expression in normal mammary
epithelial cells. Clin. Cancer Res. 6(11),
4334–4342 (2000).
74
Zhou Q, Melkoumian ZK, Lucktong A et al.
Rapid induction of histone hyperacetylation
and cellular differentiation in human breast
tumor cell lines following degradation of
histone deacetylase-1. J. Biol. Chem. 275(45),
35256–35263 (2000).
75
Wang S, Yan-Neale Y, Cai R, Alimov I,
Cohen D. Activation of mitochondrial
pathway is crucial for tumor selective
induction of apoptosis by LAQ824. Cell Cycle
5(15), 1662–1668 (2006).
76
Johnstone RW, Licht JD. Histone deacetylase
inhibitors in cancer therapy: is transcription
the primary target? Cancer Cell 4(1), 13–18
(2003).
77
Peart MJ, Tainton KM, Ruefli AA et al. Novel
mechanisms of apoptosis induced by histone
deacetylase inhibitors. Cancer Res. 63(15),
4460–4471 (2003).
78
Marks PA, Richon VM, Rifkind RA. Histone
deacetylase inhibitors: inducers of
differentiation or apoptosis of transformed
cells. J. Natl Cancer Inst. 92(15), 1210–1216
(2000).
79
Rosato RR, Almenara JA, Dai Y, Grant S.
Simultaneous activation of the intrinsic and
extrinsic pathways by histone deacetylase
(HDAC) inhibitors and tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL)
synergistically induces mitochondrial damage
and apoptosis in human leukemia cells. Mol.
Cancer Ther. 2(12), 1273–1284 (2003).
80
Zhao Y, Tan J, Zhuang L et al. Inhibitors of
histone deacetylases target the Rb-E2F1
pathway for apoptosis induction through
activation of proapoptotic protein Bim. Proc.
Natl Acad. Sci. USA 102(44), 16090–16095
(2005).
81
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.
67(4), 1166–1176 (2005).
82
Sawa H, Murakami H, Ohshima Y et al.
Histone deacetylase inhibitors such as sodium
butyrate and trichostatin A induce apoptosis
through an increase of the bcl-2-related
protein Bad. Brain Tumor Pathol. 18(2),
109–114 (2001).
593
Marchion & Münster
83
84
85
86
87
88
89
90
91
92
Strait KA, Warnick CT, Ford CD et al.
Histone deacetylase inhibitors induce
G2-checkpoint arrest and apoptosis in
cisplatinum-resistant ovarian cancer cells
associated with overexpression of the
Bcl-2-related protein Bad. Mol. Cancer Ther.
4(4), 603–611 (2005).
93
Wei Y, Yu L, Bowen J, Gorovsky MA,
Allis CD. Phosphorylation of histone H3
is required for proper chromosome
condensation and segregation. Cell 97(1),
99–109 (1999).
94
Hayakawa T, Haraguchi T, Masumoto H,
Hiraoka Y. Cell cycle behavior of human
HP1 subtypes: distinct molecular domains
of HP1 are required for their centromeric
localization during interphase and
metaphase. J. Cell Sci. 116(Pt 16),
3327–3338 (2003).
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. 11(17),
6382–6389 (2005).
Sutheesophon K, Kobayashi Y, Takatoku MA
et al. Histone deacetylase inhibitor
depsipeptide (FK228) induces apoptosis in
leukemic cells by facilitating mitochondrial
translocation of Bax, which is enhanced by
the proteasome inhibitor bortezomib. Acta
Haematol. 115(1–2), 78–90 (2006).
Cao XX, Mohuiddin I, Ece F,
McConkey DJ, Smythe WR. Histone
deacetylase inhibitor downregulation of bcl-xl
gene expression leads to apoptotic cell death
in mesothelioma. Am. J. Respir. Cell Mol.
Biol. 25(5), 562–568 (2001).
Shankar S, Singh TR, Fandy TE et al.
Interactive effects of histone deacetylase
inhibitors and TRAIL on apoptosis in
human leukemia cells: involvement of both
death receptor and mitochondrial
pathways. Int. J. Mol. Med. 16(6),
1125–1138 (2005).
Zhang XD, Gillespie SK, Borrow JM,
Hersey P. The histone deacetylase inhibitor
suberic bishydroxamate regulates the
expression of multiple apoptotic mediators
and induces mitochondria-dependent
apoptosis of melanoma cells. Mol. Cancer
Ther. 3(4), 425–435 (2004).
Muhlethaler-Mottet A, Flahaut M, Bourloud
KB et al. Histone deacetylase inhibitors
strongly sensitise neuroblastoma cells to
TRAIL-induced apoptosis by a caspasesdependent increase of the pro- to antiapoptotic proteins ratio. BMC Cancer 6, 214
(2006).
Kim HR, Kim EJ, Yang SH et al.
Trichostatin A induces apoptosis in lung
cancer cells via simultaneous activation of the
death receptor-mediated and mitochondrial
pathway? Exp. Mol. Med. 38(6), 616–624
(2006).
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.
11(1), 71–76 (2005).
Hirano T. The ABCs of SMC proteins:
two-armed ATPases for chromosome
condensation, cohesion, and repair.
Genes Dev. 16(4), 399–414 (2002).
594
95
96
97
Noma K, Sugiyama T, Cam H et al. RITS
acts in cis to promote RNA
interference-mediated transcriptional and
post-transcriptional silencing. Nat. Genet.
36(11), 1174–1180 (2004).
Carmeliet P, Dor Y, Herbert JM et al.
Role of HIF-1α in hypoxia-mediated
apoptosis, cell proliferation and tumour
angiogenesis. Nature 394(6692), 485–490
(1998).
Nor JE, Christensen J, Mooney DJ,
Polverini PJ. Vascular endothelial growth
factor (VEGF)-mediated angiogenesis is
associated with enhanced endothelial cell
survival and induction of Bcl-2 expression.
Am. J. Pathol. 154(2), 375–384 (1999).
98
Kim MS, Kwon HJ, Lee YM et al.
Histone deacetylases induce angiogenesis
by negative regulation of tumor
suppressor genes. Nat. Med. 7(4),
437–443 (2001).
99
Deroanne CF, Bonjean K, Servotte S et al.
Histone deacetylases inhibitors as
anti-angiogenic agents altering vascular
endothelial growth factor signaling.
Oncogene 21(3), 427–436 (2002).
100
Rossig L, Li H, Fisslthaler B et al.
Inhibitors of histone deacetylation
downregulate the expression of
endothelial nitric oxide synthase and
compromise endothelial cell function in
vasorelaxation and angiogenesis. Circ. Res.
91(9), 837–844 (2002).
101
Kwon HJ, Kim MS, Kim MJ,
Nakajima H, Kim KW. Histone
deacetylase inhibitor FK228 inhibits
tumor angiogenesis. Int. J. Cancer 97(3),
290–296 (2002).
102
Pili R, Kruszewski MP, Hager BW,
Lantz J, Carducci MA. Combination of
phenylbutyrate and 13-cis retinoic acid
inhibits prostate tumor growth and
angiogenesis. Cancer Res. 61(4),
1477–1485 (2001).
103
Qian DZ, Kato Y, Shabbeer S et al.
Targeting tumor angiogenesis with histone
deacetylase inhibitors: the hydroxamic
acid derivative LBH589. Clin. Cancer Res.
12(2), 634–642 (2006).
104
Qian DZ, Wang X, Kachhap SK et al.
The histone deacetylase inhibitor
NVP-LAQ824 inhibits angiogenesis and
has a greater antitumor effect in
combination with the vascular endothelial
growth factor receptor tyrosine kinase
inhibitor PTK787/ZK222584. Cancer Res.
64(18), 6626–6634 (2004).
105
Huang N, Katz JP, Martin DR, Wu GD.
Inhibition of IL-8 gene expression in
Caco-2 cells by compounds which induce
histone hyperacetylation. Cytokine 9(1),
27–36 (1997).
106
Koyama Y, Adachi M, Sekiya M,
Takekawa M, Imai K. Histone deacetylase
inhibitors suppress IL-2-mediated gene
expression prior to induction of apoptosis.
Blood 96(4), 1490–1495 (2000).
107
Takahashi I, Miyaji H, Yoshida T, Sato S,
Mizukami T. Selective inhibition of IL-2
gene expression by trichostatin A, a potent
inhibitor of mammalian histone
deacetylase. J. Antibiot. (Tokyo) 49(5),
453–457 (1996).
108
Blanchard F, Chipoy C. Histone deacetylase
inhibitors: new drugs for the treatment of
inflammatory diseases? Drug Discov. Today
10(3), 197–204 (2005).
109
Dinarello CA. Inhibitors of histone
deacetylases as anti-inflammatory drugs.
Ernst Schering Res. Found. Workshop 56,
45–60 (2006).
110
Camelo S, Iglesias AH, Hwang D et al.
Transcriptional therapy with the histone
deacetylase inhibitor trichostatin A
ameliorates experimental autoimmune
encephalomyelitis. J. Neuroimmunol.
164(1–2), 10–21 (2005).
111
Chung YL, Lee MY, Wang AJ, Yao LF.
A therapeutic strategy uses histone
deacetylase inhibitors to modulate the
expression of genes involved in the
pathogenesis of rheumatoid arthritis.
Mol. Ther. 8(5), 707–717 (2003).
112
Reddy P, Maeda Y, Hotary K et al. Histone
deacetylase inhibitor suberoylanilide
hydroxamic acid reduces acute graft-versushost disease and preserves graft-versusleukemia effect. Proc. Natl Acad. Sci. USA
101(11), 3921–3926 (2004).
113
Brogdon J, Xu Y, Szabo S et al. Histone
deacetylase activities are required for innate
immune cell control of Th1 but not Th2
effector cell function. Blood 109(3),
1123–1130 (2007).
114
Leoni F, Zaliani A, Bertolini G et al.
The antitumor histone deacetylase inhibitor
suberoylanilide hydroxamic acid exhibits
antiinflammatory properties via suppression
of cytokines. Proc. Natl Acad. Sci. USA
99(5), 2995–3000 (2002).
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
115
Mishra N, Reilly CM, Brown DR, Ruiz P,
Gilkeson GS. Histone deacetylase
inhibitors modulate renal disease in the
MRL-lpr/lpr mouse. J. Clin. Invest. 111(4),
539–552 (2003).
128
Nusinzon I, Horvath CM. Interferonstimulated transcription and innate antiviral
immunity require deacetylase activity and
histone deacetylase 1. Proc. Natl Acad. Sci.
USA 100(25), 14742–14747 (2003).
140
Maggio SC, Rosato RR, Kramer LB et al.
The histone deacetylase inhibitor MS-275
interacts synergistically with fludarabine to
induce apoptosis in human leukemia cells.
Cancer Res. 64(7), 2590–2600 (2004).
116
Suuronen T, Huuskonen J, Pihlaja R,
Kyrylenko S, Salminen A. Regulation of
microglial inflammatory response by
histone deacetylase inhibitors.
J. Neurochem. 87(2), 407–416
(2003).
129
Vries RG, Prudenziati M, Zwartjes C et al.
A specific lysine in c-Jun is required for
transcriptional repression by E1A and is
acetylated by p300. EMBO J. 20(21),
6095–6103 (2001).
141
130
117
Ito K, Lim S, Caramori G et al.
A molecular mechanism of action of
theophylline: induction of histone
deacetylase activity to decrease
inflammatory gene expression. Proc. Natl
Acad. Sci. USA 99(13), 8921–8926 (2002).
Glozak MA, Sengupta N, Zhang X, Seto E.
Acetylation and deacetylation of
non-histone proteins. Gene 363, 15–23
(2005).
Adachi M, Zhang Y, Zhao X et al. Synergistic
effect of histone deacetylase inhibitors FK228
and m-carboxycinnamic acid bis-hydroxamide
with proteasome inhibitors PSI and PS-341
against gastrointestinal adenocarcinoma cells.
Clin. Cancer Res. 10(11), 3853–3862 (2004).
142
Bai J, Demirjian A, Sui J, Marasco W,
Callery MP. Histone deacetylase inhibitor
trichostatin A and proteasome inhibitor
PS-341 synergistically induce apoptosis in
pancreatic cancer cells. Biochem. Biophys. Res.
Commun. 348(4), 1245–1253 (2006).
143
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. 10(11),
3839–3852 (2004).
144
Yu C, Rahmani M, Conrad D et al.
The proteasome inhibitor bortezomib
interacts synergistically with histone
deacetylase inhibitors to induce apoptosis in
Bcr/Abl+ cells sensitive and resistant to
STI571. Blood 102(10), 3765–3774 (2003).
118
119
Blanchard F, Kinzie E, Wang Y et al.
FR901228, an inhibitor of histone
deacetylases, increases the cellular
responsiveness to IL-6 type cytokines by
enhancing the expression of receptor
proteins. Oncogene 21(41), 6264–6277
(2002).
Kouzarides T. Acetylation: a regulatory
modification to rival phosphorylation?
EMBO J. 19(6), 1176–1179 (2000).
131
132
Piacentini P, Donadelli M, Costanzo C et al.
Trichostatin A enhances the response of
chemotherapeutic agents in inhibiting
pancreatic cancer cell proliferation. Virchows
Arch. 448(6), 797–804 (2006).
Sato T, Suzuki M, Sato Y, Echigo S,
Rikiishi H. Sequence-dependent interaction
between cisplatin and histone deacetylase
inhibitors in human oral squamous cell
carcinoma cells. Int. J. Oncol. 28(5),
1233–1241 (2006).
133
Zhang X, Yashiro M, Ren J, Hirakawa K.
Histone deacetylase inhibitor, trichostatin
A, increases the chemosensitivity of
anticancer drugs in gastric cancer cell lines.
Oncol. Rep. 16(3), 563–568 (2006).
145
Chobanian NH, Greenberg VL, Gass JM
et al. Histone deacetylase inhibitors enhance
paclitaxel-induced cell death in ovarian
cancer cell lines independent of p53 status.
Anticancer Res. 24(2B), 539–545 (2004).
Coffey DC, Kutko MC, Glick RD et al.
Histone deacetylase inhibitors and retinoic
acids inhibit growth of human neuroblastoma
in vitro. Med. Pediatr. Oncol. 35(6), 577–581
(2000).
146
Kuendgen A, Schmid M, Schlenk R et al.
The histone deacetylase (HDAC) inhibitor
valproic acid as monotherapy or in
combination with all-trans retinoic acid in
patients with acute myeloid leukemia. Cancer
106(1), 112–119 (2006).
147
Kuendgen A, Strupp C, Aivado M et al.
Treatment of myelodysplastic syndromes with
valproic acid alone or in combination with
all-trans retinoic acid. Blood 104(5),
1266–1269 (2004).
120
Polevoda B, Sherman F. The diversity of
acetylated proteins. Genome Biol. 3(5),
reviews0006 (2002).
121
Wang R, Cherukuri P, Luo J. Activation of
Stat3 sequence-specific DNA binding and
transcription by p300/CREB-binding
protein-mediated acetylation. J. Biol.
Chem. 280(12), 11528–11534 (2005).
134
122
Yuan ZL, Guan YJ, Chatterjee D,
Chin YE. Stat3 dimerization regulated by
reversible acetylation of a single lysine
residue. Science 307(5707), 269–273
(2005).
135
123
Martinez-Balbas MA, Bauer UM,
Nielsen SJ, Brehm A, Kouzarides T.
Regulation of E2F1 activity by acetylation.
EMBO J. 19(4), 662–671 (2000).
Marchion DC, Bicaku E, Daud AI,
Sullivan DM, Munster PN. In vivo synergy
between topoisomerase II and histone
deacetylase inhibitors: predictive correlates.
Mol. Cancer Ther. 4(12), 1993–2000
(2005).
136
Kim MS, Blake M, Baek JH et al. Inhibition
of histone deacetylase increases cytotoxicity
to anticancer drugs targeting DNA. Cancer
Res. 63(21), 7291–7300 (2003).
137
Johnson CA, Padget K, Austin CA,
Turner BM. Deacetylase activity associates
with topoisomerase II and is necessary for
etoposide-induced apoptosis. J. Biol. Chem.
276(7), 4539–4542 (2001).
148
Bug G, Ritter M, Wassmann B et al. Clinical
trial of valproic acid and all-trans retinoic acid
in patients with poor-risk acute myeloid
leukemia. Cancer 104(12), 2717–2725
(2005).
138
Bevins RL, Zimmer SG. It’s about time:
scheduling alters effect of histone
deacetylase inhibitors on
camptothecin-treated cells. Cancer Res.
65(15), 6957–6966 (2005).
149
Massart C, Denais A, Gibassier J. Effect of alltrans retinoic acid and sodium butyrate
in vitro and in vivo on thyroid carcinoma
xenografts. Anticancer Drugs 17(5), 559–563
(2006).
139
Acharya MR, Figg WD. Histone
deacetylase inhibitor enhances the
anti-leukemic activity of an established
nucleoside analogue. Cancer Biol. Ther.
3(8), 719–720 (2004).
150
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. 21(1), 103–107
(1999).
124
125
126
127
Marzio G, Wagener C, Gutierrez MI et al.
E2F family members are differentially
regulated by reversible acetylation. J. Biol.
Chem. 275(15), 10887–10892 (2000).
Gu W, Roeder RG. Activation of p53
sequence-specific DNA binding by
acetylation of the p53 C-terminal domain.
Cell 90(4), 595–606 (1997).
Sykes SM, Mellert HS, Holbert MA et al.
Acetylation of the p53 DNA-binding
domain regulates apoptosis induction.
Mol. Cell 24(6), 841–851 (2006).
Kramer OH, Baus D, Knauer SK et al.
Acetylation of Stat1 modulates NF-κB
activity. Genes Dev. 20(4), 473–485
(2006).
www.future-drugs.com
595
Marchion & Münster
151
Gore SD, Baylin S, Sugar E et al.
Combined DNA methyltransferase and
histone deacetylase inhibition in the
treatment of myeloid neoplasms. Cancer
Res. 66(12), 6361–6369 (2006).
152
Hurtubise A, Momparler RL. Effect of
histone deacetylase inhibitor LAQ824 on
antineoplastic action of 5-aza2´-deoxycytidine (decitabine) on human
breast carcinoma cells. Cancer Chemother.
Pharmacol. 58(5), 618–625 (2006).
162
Senyuk V, Chakraborty S, Mikhail FM
et al. The leukemia-associated transcription
repressor AML1/MDS1/EVI1 requires
CtBP to induce abnormal growth and
differentiation of murine hematopoietic
cells. Oncogene 21(20), 3232–3240 (2002).
163
Minucci S, Horn V, Bhattacharyya N et al.
A histone deacetylase inhibitor potentiates
retinoid receptor action in embryonal
carcinoma cells. Proc. Natl Acad. Sci. USA
94(21), 11295–11300 (1997).
153
Zhu WG, Lakshmanan RR, Beal MD,
Otterson GA. DNA methyltransferase
inhibition enhances apoptosis induced by
histone deacetylase inhibitors. Cancer Res.
61(4), 1327–1333 (2001).
164
He LZ, Guidez F, Tribioli C et al. Distinct
interactions of PML–RARα and
PLZF–RARα with co-repressors determine
differential responses to RA in APL. Nat.
Genet. 18(2), 126–135 (1998).
154
Camphausen K, Burgan W, Cerra M et al.
Enhanced radiation-induced cell killing
and prolongation of γH2AX foci expression
by the histone deacetylase inhibitor
MS-275. Cancer Res. 64(1), 316–321
(2004).
165
Lin RJ, Nagy L, Inoue S et al. Role of the
histone deacetylase complex in acute
promyelocytic leukaemia. Nature
391(6669), 811–814 (1998).
166
Duvic M, Talpur R, Ni X et al. Phase II
trial of oral vorinostat (suberoylanilide
hydroxamic acid, SAHA) for refractory
cutaneous T-cell lymphoma (CTCL).
Blood 109(1), 31–39 (2007).
155
Flatmark K, Nome RV, Folkvord S et al.
Radiosensitization of colorectal carcinoma
cell lines by histone deacetylase inhibition.
Radiat. Oncol. 1(1), 25 (2006).
156
Kim MS, Baek JH, Chakravarty D,
Sidransky D, Carrier F. Sensitization to
UV-induced apoptosis by the histone
deacetylase inhibitor trichostatin A (TSA).
Exp. Cell Res. 306(1), 94–102 (2005).
157
Zhang Y, Adachi M, Kawamura R et al.
Bmf contributes to histone deacetylase
inhibitor-mediated enhancing effects on
apoptosis after ionizing radiation. Apoptosis
11(8), 1349–1357 (2006).
158
Chen Z, Brand NJ, Chen A et al. Fusion
between a novel Kruppel-like zinc finger
gene and the retinoic acid receptor-α locus
due to a variant t(11;17) translocation
associated with acute promyelocytic
leukaemia. EMBO J. 12(3), 1161–1167
(1993).
159
160
161
de The H, Lavau C, Marchio A et al.
The PML-RAR α fusion mRNA generated
by the t(15;17) translocation in acute
promyelocytic leukemia encodes a
functionally altered RAR. Cell 66(4),
675–684 (1991).
Grignani F, De Matteis S, Nervi C et al.
Fusion proteins of the retinoic acid
receptor-α recruit histone deacetylase in
promyelocytic leukaemia. Nature
391(6669), 815–818 (1998).
Ruthardt M, Testa U, Nervi C et al.
Opposite effects of the acute promyelocytic
leukemia PML-retinoic acid receptor α
(RAR α) and PLZF-RAR α fusion proteins
on retinoic acid signalling. Mol. Cell. Biol.
17(8), 4859–4869 (1997).
596
167
Kelly WK, Richon VM, O’Connor O
et al. Phase I clinical trial of histone
deacetylase inhibitor: suberoylanilide
hydroxamic acid administered
intravenously. Clin. Cancer Res.
9(10 Pt 1), 3578–3588 (2003).
168
Cohen LA, Amin S, Marks PA et al.
Chemoprevention of carcinogen-induced
mammary tumorigenesis by the hybrid
polar cytodifferentiation agent,
suberanilohydroxamic acid (SAHA).
Anticancer Res. 19(6B), 4999–5005
(1999).
169
170
Kelly WK, O’Connor OA, Krug LM et al.
Phase I study of an oral histone deacetylase
inhibitor, suberoylanilide hydroxamic
acid, in patients with advanced cancer.
J. Clin. Oncol. 23(17), 3923–3931 (2005).
O’Connor OA, Heaney ML, Schwartz L
et al. Clinical experience with intravenous
and oral formulations of the novel histone
deacetylase inhibitor suberoylanilide
hydroxamic acid in patients with advanced
hematologic malignancies. J. Clin. Oncol.
24(1), 166–173 (2006).
171
Sandor V, Bakke S, Robey RW et al.
Phase I trial of the histone deacetylase
inhibitor, depsipeptide (FR901228, NSC
630176), in patients with refractory
neoplasms. Clin. Cancer Res. 8(3),
718–728 (2002).
172
Marshall JL, Rizvi N, Kauh J et al.
A Phase I trial of depsipeptide
(FR901228) in patients with advanced
cancer. J. Exp. Ther. Oncol. 2(6), 325–332
(2002).
173
Piekarz RL, Frye AR, Wright JJ et al.
Cardiac studies in patients treated with
depsipeptide, FK228, in a Phase II trial for
T-cell lymphoma. Clin. Cancer Res. 12(12),
3762–3773 (2006).
174
Stadler WM, Margolin K, Ferber S,
McCulloch W, Thompson JA. A Phase II
study of depsipeptide in refractory
metastatic renal cell cancer. Clin.
Genitourin. Cancer 5(1), 57–60 (2006).
175
Shah MH, Binkley P, Chan K et al.
Cardiotoxicity of histone deacetylase
inhibitor depsipeptide in patients with
metastatic neuroendocrine tumors.
Clin. Cancer Res. 12(13), 3997–4003
(2006).
176
Fouladi M, Furman WL, Chin T et al.
Phase I study of depsipeptide in pediatric
patients with refractory solid tumors: a
Children’s Oncology Group report. J. Clin.
Oncol. 24(22), 3678–3685 (2006).
177
Gottlicher M. Valproic acid: an old drug
newly discovered as inhibitor of histone
deacetylases. Ann. Hematol. 83(Suppl. 1),
S91–S92 (2004).
178
Gottlicher M, Minucci S, Zhu P et al.
Valproic acid defines a novel class of
HDAC inhibitors inducing differentiation
of transformed cells. EMBO J. 20(24),
6969–6978 (2001).
179
Gurvich N, Tsygankova OM,
Meinkoth JL, Klein PS. Histone
deacetylase is a target of valproic acidmediated cellular differentiation. Cancer
Res. 64(3), 1079–1086 (2004).
180
Williams RS, Cheng L, Mudge AW,
Harwood AJ. A common mechanism of
action for three mood-stabilizing drugs.
Nature 417(6886), 292–295 (2002).
181
Phiel CJ, Zhang F, Huang EY et al.
Histone deacetylase is a direct target of
valproic acid, a potent anticonvulsant,
mood stabilizer, and teratogen. J. Biol.
Chem. 276(39), 36734–36741 (2001).
182
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. 29(7), 739–748 (2005).
183
Garcia-Manero G, Kantarjian HM,
Sanchez-Gonzalez B et al. Phase I/II study
of the combination of
5-aza-2´-deoxycytidine with valproic acid
in patients with leukemia. Blood 108(10),
3271–3279 (2006).
184
Atadja P, Hsu M, Kwon P et al. Molecular
and cellular basis for the anti-proliferative
effects of the HDAC inhibitor LAQ824.
Novartis Found. Symp. 259, 249–266;
discussion 266–268, 285–288 (2004).
Expert Rev. Anticancer Ther. 7(4), (2007)
Histone deacetylase inhibitors and cancer
185
186
187
188
189
190
191
192
193
194
195
Bali P, Pranpat M, Bradner J et al.
Inhibition of histone deacetylase 6
acetylates and disrupts the chaperone
function of heat shock protein 90: a novel
basis for antileukemia activity of histone
deacetylase inhibitors. J. Biol. Chem.
280(29), 26729–26734 (2005).
Giles F, Fischer T, Cortes J et al. A Phase I
study of intravenous LBH589, a novel
cinnamic hydroxamic acid analogue histone
deacetylase inhibitor, in patients with
refractory hematologic malignancies. Clin.
Cancer Res. 12(15), 4628–4635 (2006).
Ryan QC, Headlee D, Acharya M et al.
Phase I and pharmacokinetic study of
MS-275, a histone deacetylase inhibitor, in
patients with advanced and refractory solid
tumors or lymphoma. J. Clin. Oncol.
23(17), 3912–3922 (2005).
Gilbert J, Baker SD, Bowling MK et al.
A Phase I dose escalation and bioavailability
study of oral sodium phenylbutyrate in
patients with refractory solid tumor
malignancies. Clin. Cancer Res. 7(8),
2292–2300 (2001).
Plumb JA, Finn PW, Williams RJ et al.
Pharmacodynamic response and inhibition
of growth of human tumor xenografts by
the novel histone deacetylase inhibitor
PXD101. Mol. Cancer Ther. 2(8), 721–728
(2003).
Qian X, LaRochelle WJ, Ara G et al.
Activity of PXD101, a histone deacetylase
inhibitor, in preclinical ovarian cancer
studies. Mol. Cancer Ther. 5(8), 2086–2095
(2006).
Munster PN, Marchion DC, Bicaku E et al.
Phase I trial of histone deacetylase
inhibition by valproic acid (VPA) followed
by the topoisomerase II inhibitor
epirubicin in advanced solid tumors: a
clinical and translational study. J. Clin.
Oncol. (2007) (In Press).
Laherty CD, Yang WM, Sun JM et al.
Histone deacetylases associated with the
mSin3 corepressor mediate mad
transcriptional repression. Cell 89(3),
349–356 (1997).
Hassig CA, Fleischer TC, Billin AN,
Schreiber SL, Ayer DE. Histone deacetylase
activity is required for full transcriptional
repression by mSin3A. Cell 89(3), 341–347
(1997).
Nagy L, Kao HY, Chakravarti D et al.
Nuclear receptor repression mediated by a
complex containing SMRT, mSin3A, and
histone deacetylase. Cell 89(3), 373–380
(1997).
Humphrey GW, Wang Y, Russanova VR
et al. Stable histone deacetylase complexes
distinguished by the presence of SANT
www.future-drugs.com
complex containing HDAC3 and
SMRT/N-CoR. Mol. Cell 9(1), 45–57
(2002).
domain proteins CoREST/kiaa0071 and
Mta-L1. J. Biol. Chem. 276(9),
6817–6824 (2001).
196
197
198
199
200
201
202
You A, Tong JK, Grozinger CM, Schreiber
SL. CoREST is an integral component of
the CoREST–human histone deacetylase
complex. Proc. Natl Acad. Sci. USA 98(4),
1454–1458 (2001).
Glaser KB, Li J, Staver MJ et al. Role of
class I and class II histone deacetylases in
carcinoma cells using siRNA. Biochem.
Biophys. Res. Commun. 310(2), 529–536
(2003).
Lehrmann H, Pritchard LL, Harel-Bellan A.
Histone acetyltransferases and deacetylases
in the control of cell proliferation and
differentiation. Adv. Cancer Res. 86, 41–65
(2002).
Calonghi N, Cappadone C, Pagnotta E
et al. Histone deacetylase 1: a target of
9-hydroxystearic acid in the inhibition of
cell growth in human colon cancer.
J. Lipid Res. 46(8), 1596–1603 (2005).
Lagger G, O’Carroll D, Rembold M et al.
Essential function of histone deacetylase 1
in proliferation control and CDK
inhibitor repression. EMBO J. 21(11),
2672–2681 (2002).
Stadler JA, Shkumatava A, Norton WH
et al. Histone deacetylase 1 is required for
cell cycle exit and differentiation in the
zebrafish retina. Dev. Dyn. 233(3),
883–889 (2005).
Huang BH, Laban M, Leung CH et al.
Inhibition of histone deacetylase 2
increases apoptosis and p21Cip1/WAF1
expression, independent of histone
deacetylase 1. Cell Death Differ. 12(4),
395–404 (2005).
203
Hrzenjak A, Moinfar F, Kremser ML et al.
Valproate inhibition of histone
deacetylase 2 affects differentiation and
decreases proliferation of endometrial
stromal sarcoma cells. Mol. Cancer Ther.
5(9), 2203–2210 (2006).
204
Wilson AJ, Byun DS, Popova N 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. 281(19), 13548–13558
(2006).
205
206
Fischle W, Dequiedt F, Fillion M et al.
Human HDAC7 histone deacetylase
activity is associated with HDAC3 in vivo.
J. Biol. Chem. 276(38), 35826–35835
(2001).
Fischle W, Dequiedt F, Hendzel MJ et al.
Enzymatic activity associated with class II
HDACs is dependent on a multiprotein
207
Hug BA. HDAC4: a corepressor
controlling bone development. Cell
119(4), 448–449 (2004).
208
Dressel U, Bailey PJ, Wang SC et al.
A dynamic role for HDAC7 in
MEF2-mediated muscle differentiation.
J. Biol. Chem. 276(20), 17007–17013
(2001).
209
McKinsey TA, Zhang CL, Lu J,
Olson EN. Signal-dependent nuclear
export of a histone deacetylase regulates
muscle differentiation. Nature 408(6808),
106–111 (2000).
210
Miska EA, Langley E, Wolf D et al.
Differential localization of HDAC4
orchestrates muscle differentiation.
Nucleic Acids Res. 29(16), 3439–3447
(2001).
211
Hubbert C, Guardiola A, Shao R et al.
HDAC6 is a microtubule-associated
deacetylase. Nature 417(6887), 455–458
(2002).
212
Kovacs JJ, Hubbert C, Yao TP.
The HDAC complex and cytoskeleton.
Novartis Found. Symp. 259, 170–177;
discussion 178–181, 223–225 (2004).
213
Matsuyama A, Shimazu T, Sumida Y et al.
In vivo destabilization of dynamic
microtubules by HDAC6-mediated
deacetylation. EMBO J. 21(24),
6820–6831 (2002).
214
Chang S, Young BD, Li S et al. Histone
deacetylase 7 maintains vascular integrity
by repressing matrix metalloproteinase
10. Cell 126(2), 321–334 (2006).
215
Waltregny D, De Leval L, Glenisson W
et al. Expression of histone deacetylase 8,
a class I histone deacetylase, is restricted
to cells showing smooth muscle
differentiation in normal human tissues.
Am. J. Pathol. 165(2), 553–564 (2004).
216
Waltregny D, Glenisson W, Tran SL et al.
Histone deacetylase HDAC8 associates
with smooth muscle α-actin and is
essential for smooth muscle cell
contractility. FASEB J. 19(8), 966–968
(2005).
217
Kramer OH, Zhu P, Ostendorff HP et al.
The histone deacetylase inhibitor valproic
acid selectively induces proteasomal
degradation of HDAC2. EMBO J.
22(13), 3411–3420 (2003).
218
Hu E, Dul E, Sung CM et al.
Identification of novel isoform-selective
inhibitors within class I histone
deacetylases. J. Pharmacol. Exp. Ther.
307(2), 720–728 (2003).
597
Marchion & Münster
219
Ropero S, Fraga MF, Ballestar E et al.
A truncating mutation of HDAC2 in
human cancers confers resistance to
histone deacetylase inhibition. Nat. Genet.
38(5), 566–569 (2006).
Website
301
US National Institutes of Health
Clinical Trials
www.clinicaltrials.gov
598
Affiliations
•
Douglas Marchion, PhD
H Lee Moffitt Cancer Center, Experimental
Therapeutics and Breast Medical Oncology
Programs, Department of Interdisciplinary
Oncology, H Lee Moffitt Cancer Center, 12902
Magnolia Dr., Tampa, FL 33612, USA
•
Pamela Münster, MD
H Lee Moffitt Cancer Center, Experimental
Therapeutics and Breast Medical Oncology
Programs, Department of Interdisciplinary
Oncology, H Lee Moffitt Cancer Center, 12902
Magnolia Dr., Tampa, FL 33612, USA
Tel.: +1 813 745 6893
Fax: +1 813 745 1984
[email protected]
Expert Rev. Anticancer Ther. 7(4), (2007)