|Year : 2014 | Volume
| Issue : 3 | Page : 469-478
Epigenetic therapy of cancer with histone deacetylase inhibitors
KC Lakshmaiah, Linu A Jacob, S Aparna, D Lokanatha, Smitha C Saldanha
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Web Publication||14-Oct-2014|
#1472, 5th E Main Road, 1st Block, 2nd Stage, Rajajinagar, Bengaluru - 560 010, Karnataka
Source of Support: None, Conflict of Interest: None
Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III HDAC and Class IV (HDAC11). Histone Deacetylase Inhibitors (HDACI) exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates. The effects of HDACI on gene transcription are complex. They cause cell cycle arrest, inhibit DNA repair, induce apoptosis and acetylate non histone proteins causing downstream alterations in gene expression. HDACI are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two. They are classified into four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides. This review describes the clinical utility of HDACI as monotherapy as well as combination therapy with other treatment modalities such as chemotherapy and radiotherapy. Adverse effects and shortcomings of treatment with HDACI are also discussed in detail.
Keywords: Histone acetyl transferase, histone deacetylase, histone deacetylase inhibitors
|How to cite this article:|
Lakshmaiah K C, Jacob LA, Aparna S, Lokanatha D, Saldanha SC. Epigenetic therapy of cancer with histone deacetylase inhibitors. J Can Res Ther 2014;10:469-78
|How to cite this URL:|
Lakshmaiah K C, Jacob LA, Aparna S, Lokanatha D, Saldanha SC. Epigenetic therapy of cancer with histone deacetylase inhibitors. J Can Res Ther [serial online] 2014 [cited 2019 Oct 19];10:469-78. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/469/137937
| > Introduction|| |
Ever since the discovery of the structure of DNA in 1960s, the understanding of human genetics has revolutionized the field of medical oncology. More recently several epigenetic mechanisms of oncogenesis have been dissected out to its finer detail. Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Epigenetic processes ensure the effective packaging of the genetic material to fit within the mammalian nucleus. DNA is wrapped around a core of eight histone proteins to form a nucleosome, which is the building block of chromatin [Figure 1]. ,
|Figure 1: Regulation of gene expression by histone acetylation. Upper panel depicts the structure of nucleosome (DNA strand wound around histone octamer). Lower panel shows the effect of acetylation of histones (brown triangles) by histone acetyl transferase enzyme which repels the histone away from DNA and exposes histone free DNA for gene expression|
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| > Role of chromatin in gene regulation|| |
Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling (NuRD) and histone covalent modifications.
| > Dna methylation|| |
Many human genes contain CpG rich regions (CpG islands) at their transcription start sites and are normally unmethylated. Methylation of cytosine of a CpG dinucleotide by DNA methyl transferase enzyme results in repression of gene expression.  Aberrant methylation of tumor suppressor genes is one of the earliest events in the initiation of tumorigenesis.
| > Nucleosomal remodelling|| |
The relative position of the nucleosomes along the DNA strand is governed by ATP dependent multiprotein chromatin remodeling complexes. , These complexes reposition the nucleosomes along the DNA by sliding or ejecting the histones and create nucleosome-free regions of DNA, which are accessible to transcription factors and lead to gene activation. Conversely, restructuring of nucleosomes in the form of the loop or addition of histones would lead to compact conformation of chromatin and gene repression.
Histone covalent modifications
Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and thereby alter gene expression. Among the histone covalent modifications histone acetylation is the most well understood. The enzyme histone acetyl transferase (HAT) acetylates lysine residues at the N terminus of histone protein and histone deacetylase (HDAC) removes acetyl groups from histone.  These chemical modifications on the histones form the basis for "histone code." Such histone modifications may be associated with gene expression or gene silencing. For example, acetylation of lysine 9 on histone 3 is associated with gene activation whereas acetylation of lysine 16 on histone 4 leads to gene repression.
The three epigenetic processes discussed above are closely interlinked. Cytosine methylation attracts HDACs and methylated DNA-binding proteins to CpG sites during chromatin compaction and gene silencing. DNA methylation binding protein 2 interacts with NuRD complex and directs the complex to methylated DNA. Since gene expression requires both demethylation and histone acetylation, combinations of drugs that alter both processes may be more effective in treating cancer. Since many pathways relevant to cancer development are silenced simultaneously by epigenetic mechanisms, epigenetic therapy has the potential to reactivate them all. The efficacy of epigenetic therapy may also be enhanced through the combination with other treatment modalities like radiotherapy or chemotherapy.
Many cancers display molecular alterations that hamper the balance between HAT and HDAC activity. HDACs exert a pro-oncogenic effect by keeping genes involved in differentiation, apoptosis and cell cycle arrest in a transcriptionally quiescent state. ,, Mutations of HAT proteins have been identified in colorectal, breast, prostate, gastric and ovarian cancer. ,,, Therefore, the inhibition of HDACs is a rational target for the development of novel anticancer therapy.
| > Classification of histone deacetylase|| |
The HDAC enzymes appear to be the major target of the histone deacetylase inhibitors (HDACIs) and are grouped into four different classes based on their similarity to known yeast HDACs [Table 1]. , Class I HDAC isoenzymes include HDAC1, HDAC2, HDAC3 and HDAC8 and are homologous to the yeast RPD3 protein; class II HDAC isoenzymes such as HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10 are homologous to the yeast HDA1 protein and class III HDACs are similar to the yeast SIR2 proteins. Class IV contains only HDAC11.
| > Mechanism of action of histone deacetylase inhibitors|| |
Histone deacetylase inhibitors promote acetylation of histone which neutralizes the positive charge of the histone tails and reduces the affinity of histone for the negatively charged DNA. This loosens the structure of the chromatin to an open configuration which enables the transcriptional machinery to access the DNA and enhance gene transcription [Figure 1]. Secondly, HDACIs promote acetylation of non-histone protein substrates, such as DNA-binding proteins, transcription factors, signal-transduction molecules, DNA-repair proteins, and chaperone proteins. , These modifications of the non-histone proteins can affect many vital regulatory processes, including gene expression, mRNA stability, protein activity, and protein stability.  Transcriptional effects of HDACI are brought about by histone acetylation whereas apoptotic processes are modulated by non-histone protein acetylation. (e.g. p53, Hsp90 or tubulin).
The effects of HDACI on gene transcription are complex and involve multiple transcription factors and downstream alterations in gene expression. The following are the putative mechanisms of action of HDACIs [Figure 2].
Effect on cell cycle
Histone deacetylase inhibitors cause cell cycle arrest by induction of CDKN1A and its encoded protein, p21 and cyclin D and cyclin A gene repression. These events lead to phosphorylation and decreased activity of retinoblastoma protein (pRb). ,, Another cause of cell cycle arrest is acetylation of pericentromeric chromatin by HDACI and impairment of kinetochore assembly which activate mitotic check points. 
Generation of reactive oxygen species
Histone deacetylase inhibitors cause generation of reactive oxygen species followed by ceramide generation, mitochondrial injury, and activation of the caspase cascade that leads to apoptosis. ,
Acetylation of non-histone proteins
Acetylation of p53 following HDACI exposure causes decreased proteosomal degradation and induces expression of p21.  Acetylation of Hsp90 disrupts the interaction of chaperone with its client proteins. Many Hsp90 client proteins are implicated in the onset and maintenance of the malignant phenotype. Cell lines that are addicted to Hsp90 client proteins such as human epidermal growth factor receptor-2, the BCR-ABL fusion protein, or mutated and activated epidermal growth factor receptor are sensitive to both Hsp90 inhibitors and HDACIs. ,,
Inhibition of DNA repair
Histone deacetylase inhibitors impair DNA repair processes through acetylation or downregulation of proteins such as Ku70, Ku86, BRCA1, and RAD51 involved in DNA mismatch repair. This forms the basis for combination of HDACI with chemotherapy or irradiation. ,
Induction of apoptosis
Histone deacetylase inhibitors induce apoptosis by either the extrinsic (cell death receptor-mediated pathway) or the intrinsic (mitochondria-mediated pathway). Several HDACIs increase expression of TRAIL, DR-5, DR-4, Fas, and Fas-L ,, and cause apoptosis by extrinsic pathway. HDACIs facilitate the intrinsic apoptosis pathway by down regulating anti apoptotic proteins such as Bcl-2, Mcl-1 and Bcl-X L and up regulating pro apoptotic proteins such as Bim, Bax, Puma, and Noxa. ,,,
Histone deacetylase inhibitors inhibit angiogenesis by down regulating genes involved in angiogenesis, such as the vascular endothelial growth factor (VEGF) and the endothelial nitric oxide synthase (eNOS). ,, Hypoxia inducible factor-1α, a pro-angiogenic transcription factor, is hyperacetylated by HDACIs, resulting in its degradation.  This effect is the rationale for the combination of HDACIs with antiangiogenetic agents, such as bevacizumab. 
Disruption of aggresome formation
The proteosome system is widely utilized by malignant cells to degrade the misfolded proteins accumulated inside the cells during their rapid turnover. In case of impaired proteosome activity cells activate the formation of aggresome, a pathway that allows the degradation of misfolded proteins. Aggresome formation depends on the HDAC6-mediated deacetylation of α-tubulin.  HDACIs cause intracellular accumulation of misfolded proteins and as a consequence, cell apoptosis. 
| > Histone deacetylase inhibitors|| |
Histone deacetylase inhibitors are a new class of anticancer drugs that belong to the broader category of "chromatin modifying agents". By modifying the epigenetic profile and altering gene expression, HDACIs bring about multitude of effects in the downstream pathways of cells culminating in cytotoxicty. They are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two.  They can be classified into the following four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides [Table 2].
| > Short chain fatty acids|| |
Short chain fatty acids include Sodium butyrate, Phenylbutyrate and Valproic acid (VPA) which selectively inhibit class I and IIA HDACs. They require submillimolar to millimolar concentration to inhibit HDAC. Sodium butyrate and phenylbutyrate have been investigated in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and found to have limited activity. VPA has been used as an antiepileptic drug and has manageable side effect profile. In separate studies, VPA has been investigated in patients of AML or high-risk MDS in combination with demethylating agents like azacitidine and decitabine with or without all-trans retinoic acid. The studies reported variable hematologic improvement and safe combination. ,,
| > Hydroxamic acids|| |
Generally, the hydroxamates exert nonspecific HDAC-inhibition activity affecting all classes of HDACs.
Vorinostat inhibits all zinc-dependent HDACs in the low nanomolar range except HDAC IIa. It was the first HDACI approved by Food and Drug Administration (FDA) in 2006 for refractory cutaneous T-cell Lymphoma (CTCL). FDA approval was based on two phase II clinical trials with a 30% response rate in patients with CTCL. , Vorinostat showed response rates similar to previously used therapies and a higher relief from pruritus in comparison to other agents. Vorinostat is one of the most extensively studied HDACI in both hematologic and solid tumors.
| > Trials of Vorinostat in Hematologic Malignancies - Mono Therapy|| |
In a small phase I trial, 10 patients with malignant lymphoma were administered vorinostat 100 mg or 200 mg twice daily for 14 days.  Overall Response Rate (ORR) was 40% with two complete response/unconfirmed (Cru) and one partial response (PR) among follicular lymphoma patients and one Cru among mantle cell lymphoma patients. A phase II trial evaluated vorinostat in 35 patients with relapsed/refractory indolent lymphoma. ORR was 29%(five complete response (CR) and five PR).  For 17 patients with follicular lymphoma, ORR was 47% (four CR, four PR). There were two of nine responders with Marginal zone lymphoma (one CR, one PR) and no formal responders among 9 patients with Mantle cell lymphoma. Vorinostat has been evaluated in relapsed/refractory Hodgkin disease  and found to have limited activity.
| > Trials OF Vorinostat in Hematologic Malignancies - Combination Therapy|| |
In a randomized double blind placebo controlled phase III trial (VANTAGE 088), 637 patients with non-refractory multiple myeloma with progressive disease were administered Bortezomib in combination with oral vorinostat.  Median progression-free survival (PFS) was 7.63 months (95% confidence interval [CI] 6.87-8.40) in vorinostat group and 6.83 months in the placebo group (hazard ratio [HR] 0.77, 95% CI 0.64-0.94; P = 0.010) [Table 3].
|Table 3: Clinical trials of vorinostat in combination therapy in patients with hematologic malignancies |
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In a phase I dose escalation study, 29 patients with relapsed lymphoma were given oral vorinostat in combination with the standard rituximab ifosfamide-carboplatin-etoposide regimen. Responses were observed in 19 of 27 evaluable patients (70%) including 8 CR/Cru. Grade three gastrointestinal toxicity was observed in 9 patients. 
In patients with AML/MDS, vorinostat has been used in combination with Idarubicin and cytarabine  , demethylating agent decitabine  and gemtuzumab ozagamycin.  The combinations were well tolerated and were synergistic.
In a phase I/II study in 50 patients with high risk hematological malignancies undergoing related donor reduced intensity conditioning hematopoietic stem cell transplant, vorinostat in combination with standard graft versus host disease (GVHD) prophylaxis was safe and decreased the incidence of severe acute GVHD. 
| > Trials of Vorinostat in Solid Tumors - Mono Therapy|| |
In general, outcomes of trials of vorinostat as monotherapy in solid tumors have been disappointing.  More encouraging results were reported from a phase II trial of patients with recurrent glioblastoma multiforme in which 9 out of 52 patients were progression-free after 6-months. 
| > Trials of Vorinostat in Solid Tumors - Combination Therapy|| |
Vorinostat has been evaluated in several combination therapy regimens for different types of solid tumors [Table 4]. In general, the activity is higher than in the single agent trials, but in most cases it has not been shown that the higher activity results from the addition of vorinostat to standard therapy.
|Table 4: Trials of vorinostat in combination therapy in patients with solid tumors |
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In preclinical models, vorinostat is known to sensitize breast cancer cells to tubulin-polymerizing agents and to anti-VEGF-directed therapies. In a phase I/II trial, 54 patients with metastatic breast cancer were administered vorinostat in combination with paclitaxel and bevacizumab. ORR was 24 out of 54 (55%). 
Histone deacetylases are crucial components of the oestrogen receptor transcriptional complex. In a preclinical model, HDACI could reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. In a phase II trial 43 hormone therapy resistant patients with breast cancer received vorinostat along with tamoxifen. The ORR by Response Evaluation Criteria in Solid Tumors criteria was 19% and the clinical benefit rate (response or stable disease [SD] >24 weeks) was 40%. 
Preclinical data showed that Vorinostat was able to downregulate the expression of thymidylate synthase in tumor tissue. As this protein is the target enzyme of 5-fluorouracil, a synergistic effect of this combination could be demonstrated in preclinical experiments. In a phase I trial 21 patients with refractory colorectal cancer received vorinostat in combination with FOLFOX. SD was seen in 5 of 21 patients. 
Histone deacetylase inhibitors have shown radiosensitizing activity in preclinical tumor models. In a phase I trial (Pelvic Radiation and Vorinostat) 16 patients with gastrointestinal carcinoma received vorinostat in combination with pelvic radiotherapy. The combination was well- tolerated and most patients had a decrease in tumor volume 6 weeks after completion of treatment. 
| > Trials of panabinostat|| |
Panabinostat has been tested in both oral and intravenous route and has the highest inhibitory potency among the clinically evaluated hydroxamic acids [Table 5].
In a phase II trial 13 patients with Medullary thyroid cancer and differentiated thyroid cancer received oral panabinostat 20 mg 3 times a week. Seven out of 13 patients had stable disease and median progression free survivl was 3.6 months (95% CI 1.8-0.8). 
In patients with relapsed and Bortezomib refractrory multiple myeloma, Panabinostat has shown synergism with Dexamethasone and Bortezomib. ORR was 34.5% (1 near CR, 18 PR) and clinical benefit rate was 52.7%. 
| > Clinical trials of belinostat|| |
Belinostat (PXD101) is a novel and potent class I and II Hb-HDACI, active at nanomolar concentrations. In a phase II trial, role of Belinostat in women with platinum-resistant epithelial ovarian cancer (EOC) and micropapillary low malignant potential (LMP) ovarian tumors was evaluated.  Of the LMP patients, one achieved a PR (unconfirmed) and ten had stable disease whereas 9 patients with EOC had stable disease as best result [Table 5].
In a phase I/II study, Belinostat was used in combination with doxorubicin in patients with soft tissue sarcoma. Eighteen out of 25 patients (72%) in the dose-escalation phase of the study achieved disease control and 12 patients remained in disease control at the 3-month time point. 
| > Cyclic peptides|| |
Romidepsin, also known as depsipeptide, is a bicyclic peptide inhibits Class I and II HDAC enzymes. It is the second HDACI to get FDA approval for Cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease on or following two systemic therapies (2009). The FDA approval was based on two single-arm, multicenter trials in which 167 patients were treated ,, and ORR of 34% and 35% were observed. The duration of response was remarkably long; 14.9 and 13.7 months, respectively.
In a phase I trial, combination of romidepsin, bortezomib and dexamethasone was shown to elicit durable responses in patients with relapsed or refractory multiple myeloma. 
Romidepsin has shown minimal activity in solid tumors. A phase II study of 35 patients with metastatic, castration-resistant prostate cancer revealed minimal clinical activity of Romidepsin. 
| > Synthetic benzamides|| |
Benzamides include mocetinostat and entinostat. Both the compounds are class specific HDACI and selectively inhibit HDAC I [Table 6].
Mocetinostat is an oral class specific HDACI and selectively inhibits HDAC Class I. It has shown promising single-agent clinical activity in a phase II trial in patients with relapsed classical Hodgkin's lymphoma. 
In a phase II study in patients with Relapsed/Refractory MDS/AML, Mocetinostat in combination with 5 Azacytidine has shown a ORR of 61% in MDS and 32% in AML. Nearly two thirds of highest risk MDS patients achieved a best response of complete remission or complete remission with incomplete marrow recovery (Cri). 
Entinostat is another class specific HDACI which inhibits HDAC class I. The combination of Entinostat and 5-Azacytidine has been evaluated in patients with myeloid malignancies. Among 30 patients who received at least four cycles of therapy, 7 patients had a CR, 4 had a PR, and 7 patients showed hematologic improvement. 
Entinostat targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. In a randomized, placebo-controlled, phase II study in post menopausal women with ER + advanced breast cancer progressing on a nonsteroidal aromatase inhibitor, treatment with Entinostat and Exemestane improved median PFS to 4.3 months versus 2.3 months with Exemestane and Placebo (HR - 0.73; 95% CI, 0.50-1.07; one-sided P =0.055; two-sided P = 0.11). 
| > Toxicity|| |
Histone deacetylase inhibitors are generally well tolerated. The most frequently encountered toxicity is gastrointestinal although cardiac conduction abnormalities have proven lethal.
Most of patients receiving HDACI therapy experience nausea, vomiting, anorexia and hence antiemetic prophylaxis is warranted. Diarrhea, constipation, dysguesia and elevation of liver enzymes may be seen.
Electrocardiogram (ECG) changes have been reported in clinical trials with the HDACIs vorinostat, romidepsin, panobinostat, belinostat and entinostat and may be considered a class effect. ,, Although ECG changes like T wave flattening and ST segment depression occur with HDACI, myocardial wall motion and left ventricular function remain unaffected. QT prolongation and sudden death has occurred with Romidepsin and are not due to the drug per se but to the electrolyte disturbances like hypokalemia and hypomagnesemia. Serum levels of potassium and magnesium should to be monitored and any deficiency should be corrected prior to therapy with HDACI. Co administration of drugs which cause QT prolongation should be avoided.
Leukopenia, granulocytopenia, and thrombocytopenia are usually transient and rapidly reversible. Neuropsychological side effects like confusion, disorientation, ataxia, vertigo, and somnolence were noted in the early trials with the short chain fatty acids. Rarely pulmonary side effects, heralded by a cough and dyspnea, have been noted.  Elevations in serum creatinine and/or electrolyte imbalances such as hypocalcemia and hypophosphatemias have occasionally occurred in HDACI trials.
In preclinical trials in rats, HDACIs have demonstrated fetal toxicity and might cause fetal growth retardation and skeletal abnormalities and are to be avoided in pregnant women.  As these agents have the potential to reactivate viral infections, close observation is indicated in patients with HIV and hepatitis. ,
| > Therapeutic challenges|| |
It is clear that the advanced understanding of aberrant epigenetic regulatory mechanisms is providing a new opportunity for targeted therapy. However, many questions remain unanswered.
First, it is not known whether class-specific HDACIs such as mocetinostat or panspecific HDACIs such as vorinostat are more successful. Second, the changes in gene expression brought about by HDACI are associated with phenotypic and differentiation effects in solid tumors that may promote survival, rather than apoptosis. Third, the optimum dose and dosage schedule of different HDACI are yet to be explored. Four, many patients show resistance to HDACI therapy.
Five, response assessment with HDACI is complicated by the fact that responses occur gradually over several months. The standard RECIST criteria for evaluation of treatment response may not be the best suited for HDACIs. Ideally biomarkers of drug efficacy should be used to ascertain that the agents are having the predicted biologic effect and it will be imperative that tissue be available for pathologic assessment of response.
To summarize, the recent explosion of knowledge regarding epigenomic instability as the driving force behind oncogenesis provides a compelling rationale for the use of epigenetic therapies. HDACIs have expanded the armamentarium of epigenetic therapies. These pleiotropic agents are generally well tolerated and show promising results alone and in combination with conventional oncological modalities.
| > Acknowledgment|| |
Authors would like to acknowledge Mr. Kumar Sreedhara Murthy for the animation work for the figures in the article.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]