Histone deacetylase inhibitors in the treatment for multiple myeloma
Histone lysine acetylation is regulated by both histone deacetylases (HDACs) and histone acetyl transferases. Inhibition of deacetylases induces hyperacetylate of target proteins and has a crucial role in the epigenetic regulation of gene expression mediating cell survival and proliferation. Therefore, HDAC inhibitors have emerged as novel therapeutic agents for cancers, including multiple myeloma (MM). Recent studies revealed that HDAC inhibitors trigger hyperacetylation of not only histones, but also non-histone proteins regulating cell growth and survival, revealing the complexity of mechanism of action of HDAC inhibitors. Many HDAC inhibitors have already shown significant anti-MM activities in preclinical studies and are under evaluation in clinical trials.
KeywordsMultiple myeloma Histone deacetylase (HDAC) HDAC inhibitor Proteasome inhibitor
Histones are the major protein components of chromatin and have been found in the nuclei of all eukaryotic cells, where they are complexed with DNA to form the repeating structure of chromatin. Histones are relatively low molecular weight and are grouped into five major classes; two copies of H2A, one copy of H2B, H3 and H4. Each histone has different lysine (K) residues, and then their acetylation status is regulated by two key enzymes, histone acetyltransferase (HAT) and histone deacetylase (HDAC). For example, histone H3 tail has K9, K14, K18, K23, K56 which can be hyperacetylated .
Classification of histone deacetylase
Importantly, recent studies have identified more than 3000 lysine acetylation sites on 1750 proteins, and also quantified acetylation changes in response to the non-selective deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and class I-selective deacetylase inhibitor entinostat (MS-275) . Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle progression, splicing, nuclear transport, and actin nucleation. However, which HDAC isoform selectively deacetylates specific histones or non-histone proteins has not yet been elucidated.
Selected HDAC inhibitors by classes
Short-chain fatty acids
Non-selective HDAC inhibitor
Vorinostat (suberoylanilide hydroxamic acid, SAHA)
Vorinostat inhibits class I and II HDAC activity and its anti-tumor activities has been extensively studied in many types of cancers. Vorinostat directly interacts with the catalytic site of HDACs and inhibits their enzymatic activity. Inhibition of HDAC activity by vorinostat results in alteration of gene expression in various cancer cell lines, including MM . Vorinostat blocks HDAC activity in cancer cell lines in vitro with IC50s of high nM to low μM range.
LAQ824 is a hydroxamic acid and inhibits class I and II HDAC activity. LAQ824 blocks HDAC activity in cancer cell lines in vitro with IC50s of 10–150 nM ranges, indicating that anti-proliferative potency of LAQ824 is up to 200-fold higher than that of vorinostat [6, 7]. In MM, LAQ824 induces apoptosis in most cell lines and primary tumor cells from patients at IC50 of 100 nM at 24 h .
Panobinostat is also a hydroxamic acid and blocks class I and II HDAC activity. However, its inhibitory effect on class I HDAC is more potent than class II HDAC (i.e., HDAC6) compared to vorinostat. Panobinostat has been studied in various malignancies as a single agent, as well as combined with other anticancer agents [9, 10, 11, 12]. In MM, IC50 of panobinostat is 20–80 nM in most cell lines, including those resistant to conventional therapeutic agents [13, 14].
Belinostat is a hydroxamate class HDAC inhibitor  which demonstrates broad anti-tumor activity in vitro and in vivo . Belinostat inhibits various types of cancer cell growth, with IC50 from 0.2 to 0.7 μM. Belinostat has antiproliferative activity in MM cell lines, and shows additive and/or synergistic effects with conventional agents used in MM. Belinostat is being tested as monotherapy and also in combination with standard agents for treatment of MM.
Class I HDAC inhibitor
Entinostat is a benzamide class HDAC inhibitor and blocks class I HDAC activity. Entinostat shows anti-tumor activity in various types of cancers in vitro, with IC50 of between high nM to low μM range. Like other HDAC inhibitors, entinostat induces caspase-dependent apoptosis .
Romidepsine (FR901228, FK228)
Romidepsine is a natural (isolated from Chromobacterium violaceum) or synthetic compound with sequences of amino and hydroxy carboxylic acid residues. It inhibits HDAC1 and HDAC2 with IC50 of 1.6 and 3.9 nM by non-cell base and cell-based assays, respectively [18, 19, 20, 21]. In MM, romidepsine induces apoptosis both in cell lines and primary tumor cells from patients, associated with downregulation of Bcl-2, BCL-xL and Mcl-1 expression .
ACY-1215 is the first in class HDAC6-selective hydroxamate HDAC inhibitor . Previous studies have characterized the aggresome as an alternative system to the proteasome for degradation of polyubiquitinated misfolded/unfolded proteins . The aggresome pathway therefore likely provides a novel system for delivery of aggregated proteins from cytoplasm to lysosomes for degradation . In this aggresomal protein degradation pathway HDAC6 has an essential role, since it can bind both polyubiquitinated proteins and dynein motors, thereby acting to recruit protein cargo to dynein motors for transport to aggresomes [24, 26].
Other HDAC inhibitors
KD5170 is non-hydroxamate, orally bioavailable HDAC inhibitor, which significantly inhibits osteoclast formation at low μM range and also triggers apoptosis in MM cells . Suberoyl-3-aminopyridineamide hydroxamic acid (pyroxamide) belongs to the hydroxamate class and has demonstrated its anti-tumor activities against prostate cancer and rhabdomyosarcoma in vitro. CI-994 is a substituted benzamide derivative that has demonstrated significant anti-tumor activity in vitro and in vivo in a broad spectrum of tumor models [28, 29]. Although CI-994 (N-acetyl-dinaline) is a pan HDAC inhibitor, its specificity and molecular mechanisms whereby it induces cytotoxicity in tumor cells remains unclear.
Preclinical activities of HDAC inhibitors in MM
Mechanisms of action whereby HDAC inhibitors trigger anti-MM activities have not yet been fully characterized. Inhibition of histone deacetylation primarily triggers gene transcription, and therefore HDAC inhibitors induce transcription of both positive and negative regulators of cell proliferation and/or survival. Specifically, the cytotoxicity/growth inhibition induced by HDAC inhibitors is the result of relative upregulation of pro-apoptotic (growth suppressive) factors. Importantly, recent studies identify a number of lysine residues in non-histone proteins involved in modulating gene expression, DNA replication/repair, cell cycle progression, cytoskeletal reorganization, and protein chaperone activity . These findings suggest further complex mechanisms of action of anti-MM tumor activities of HDAC inhibitors.
In MM, vorinostat induces upregulation of p21WAF1, a hallmark of HDAC inhibition, and induces p53 protein expression as well as dephosphorylates Rb, followed by apoptosis. Importantly, upregulation of p21WAF1 occurs prior to p53 induction, suggesting that p21WAF1 upregulation induced by vorinostat may be independent of p53 activity . Importantly, Bcl-2 plays a crucial role regulating vorinostat-induced apoptosis in MM cells. Vorinostat does not trigger significant caspase activation; conversely, the pan-caspase inhibitor does not protect cells from vorinostat-induced cytotoxicity. Moreover, poly(ADP) ribose polymerase (PARP) is significantly cleaved by vorinostat, suggesting that vorinostat triggers caspase-independent apoptosis in MM cells . Vorinostat enhances the anti-MM activity of other therapeutic agents, including dexamethasone and immunomodulatory drugs (IMiDs). Importantly, vorinostat suppresses expression and activity of the proteasome and its subunits, providing the rationale for its use in combination with bortezomib to enhance its effect . Vorinostat enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity associated with upregulation of the proapoptotic proteins (Bim, Bak, Bax, Noxa, and PUMA) and downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL)  (Fig. 2). Most recently, Chen et al.  reported that vorinostat blocks RAD51 protein response to ionizing radiation, thereby sensitizing MM cells to radiotherapy.
Other studies have proposed additional mechanisms. For example, it is possible that each agent affects complementary survival pathways in MM cells, thereby leading to synergistic effects on growth inhibition or cytotoxicity. Specifically, it was noted that exogenous overexpression of HDAC1 caused bortezomib resistance both in vitro and in vivo, which could be reversed by the class I HDAC inhibitor romidepsin. Moreover, bortezomib downregulates the expression of class I HDACs leading to histone hyperacetylation; thereby, enhancing HDAC inhibitor-induced cytotoxicity . In addition, non-selective DAC inhibitor LAQ824 has been shown to decrease 20S proteasome activity . The ability of proteasome inhibitors to downregulate HDACs, along with the observation that HDAC inhibitor can decrease proteasome activity, may contribute to the synergistic anti-tumor activities.
MM is characterized by infiltration of malignant plasma cells in the bone marrow (BM), and is associated with bone disease (osteolytic lesion). Specifically, bone formation depends on the balance of osteoblastogenesis and osteoclastogenesis. Importantly, a number of HDAC inhibitors suppress bone resorption by inhibiting osteoclasts in vitro and in animal models of chronic inflammatory diseases. Moreover, previous studies show that bortezomib enhances osteoblastogenesis, associated with Upregulation of Runx2 expression . Therefore, combined HDAC inhibitors with bortezomib not only targets MM cells, but also could improve MM-associated bone disease. Indeed, combination treatment with a hydroxamate-based histone deacetylase inhibitor JNJ-26481585 and bortezomib shows a more pronounced decrease on tumor burden and MM bone disease in the 5T2MM model with reduction of osteoclasts and increase of osteoblasts, trabecular bone volume, and trabecular number compared with bortezomib monotherapy. This study therefore suggests that this combination therapy could be a useful strategy for the treatment of MM patients with skeletal complications . Most recently, Santo et al. demonstrated the potential beneficial role of selective HDAC6 inhibition by ACY-1215 on MM-related bone disease in vitro and in vivo (Annual Meeting of American Society of Hematology, 2012, abstract 328).
Clinical activities of HDAC inhibitors in MM
HDAC inhibitors in clinical trials in MM (selected)
Bort. + Dex
Len. + Dex
Len. + Bort. + Dex
Bort. + Doxil
Len. + Dex
Carfl. + Len. + Dex
Bort. + DOX + Dex
Mel. + Pred.
Len. + Dex
With Bort. or Bort. alone
Clinical trials of vorinostat in different type of malignancies have already been published [37, 38, 39, 40, 41]. In these studies, the maximum concentration of vorinostat in plasma (Cmax) was 1631–1649 ng/ml and 2339–2963 ng/ml after 150 and 300 mg/m2 administration, respectively . The maximum tolerated dose (MTD) of vorinostat in patients with solid tumors and hematologic malignancies treated with oral vorinostat was 400 mg qd and 200 mg bid for continuous daily dosing, respectively, and 300 mg bid for 3 consecutive days per week. The major dose-limiting toxicities (DLTs) were anorexia, dehydration, diarrhea, and fatigue . In a phase I trial of single-agent vorinostat in patients with relapsed and/or refractory MM , only 1 patient (7.7 %) demonstrated a minimal response and 9 patients (69.2 %) demonstrated disease stabilization.
Clinical trials of romidepsine for different cancer types have also been reported [42, 43, 44, 45, 46]. In a phase I study, romidepsine was administrated by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. The starting dose was 1 mg/m2, and dose escalations proceeded through a total of 8 dose levels to a maximum of 24.9 mg/m2. The MTD of romidepsine given on a day-1 and -5 schedule every 21 days is 17.8 mg/m2, with DLTs including fatigue, nausea, vomiting, transient thrombocytopenia, and neutropenia. Although cardiac toxicity was a potential concern based on preclinical data, there was no clinical toxicity . In a phase II trial of single-agent romidepsine in 13 patients with refractory MM, there was evidence of disease stabilization and resolution of disease-related symptoms, although no objective responses were observed . Overall, the activity of romidepsine as single agents has been limited, and a clearer understanding of the biological activity of these agents will help determine the ideal combination therapies for clinical development.
Panobinostat is currently most extensively studied in both preclinical studies and clinical trials in MM. In a phase Ib study of panobinostat with bortezomib, responses (≥MR) were observed in 36/47 (72 %) of patients with relapsed or relapsed and refractory MM. Based on these promising results, PANORAMA-1 study was initiated, a global randomized, double-blind, phase III study of panobinostat + bortezomib + dexamethasone vs placebo (PBO) + bortezomib + dexamethasone (San-Miguel J.F. et al. at the Annual Meeting of American Society of Clinical Oncology in 2011, abstract TPS227). In this study, patients (n = 672) with relapsed or relapsed and refractory MM (1–3 prior lines of therapy) will be enrolled. Prior bortezomib treatment is permitted; however, bortezomib-refractory MM patients are excluded.
PANORAMA-2 is a single-arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with relapsed and bortezomib-refractory MM (Alsina et al. at the Annual Meeting of American Society of Clinical Oncology 2012, abstract 8012). This study has two treatment phases: phase 1 (TP1) consists of eight 3-week cycles of panobinostat + bortezomib + dexamethasone; patients who demonstrate clinical benefit enter treatment phase 2 (TP2), which consists of four 6-week cycles of panobinostat + bortezomib + dexamethasone. The primary endpoint is overall response [≥partial response (PR)]. Fifty-five patients with bortezomib-refractory MM have been enrolled, with 10 patients ongoing and 28 in follow-up. Twenty-seven (49 %) and 36 (65 %) patients received bortezomib and dexamethasone in their most recent prior line of therapy, respectively. Eighteen patients achieved ≥PR, for an overall response rate of 33 % (1 near complete response and 17 PR); and 13 patients achieved MR, for a clinical benefit rate of 56 %. Three patients achieved a VGPR. Eighteen patients completed phase-1 and entered phase-2, and 2 have completed ≥12 cycles. Common adverse events (AEs) of any grade included thrombocytopenia (66 %), fatigue (64 %), diarrhea (62 %), nausea (58 %), dyspnea (40 %), anemia (38 %), decreased appetite (36 %), and dizziness (36 %). Common grade 3/4 AEs included thrombocytopenia (58 %), fatigue (17 %), anemia (15 %), pneumonia (15 %), neutropenia (13 %), and diarrhea (13 %). Importantly, only 1 patient (2 %) experienced grade 3/4 peripheral neuropathy.
Most recently, Richardson et al. also presented results of PANORAMA-2 study at the Annual Meeting of American Society of Hematology in 2012 (abstract 1852). In this presentation, 55 patients with bortezomib-refractory MM have been enrolled, and all patients were previously treated with bortezomib, dexamethasone, and at least 1 immunomodulatory drugs [lenalidomide (98 %), thalidomide (69 %)]. The overall response rate was 35 % [1 near complete response and 18 PR or better, with 3 patients achieving a very good partial response (VGPR)]. An additional 10 patients achieved MR, for a clinical benefit rate of 53 %. The median duration of exposure was 4.6 months. The median PFS and TTP were 4.9 months. The PFS for patients whose disease progressed on bortezomib (n = 39) and within 60 days of bortezomib (n = 16) was 4.2 and 7.6 months, respectively. In patients who achieved a response, the mean time to response was 1.7 months, and the median duration of response was 6.0 months.
A phase I/II study of ACY-1215 in relapsed/refractory MM patients was also reported by Raje et al. at the Annual Meeting of American Society of Hematology (2012, abstract 4061). In this study, 13 out of 16 patients were treated with ACY-1215 monotherapy and 3 patients were treated in combination with bortezomib. ACY-1215 monotherapy (up to 160 mg/day) was well tolerated, with no DLTs and mostly grade 1–2 AEs. The most common AEs with monotherapy were elevated creatinine, diarrhea, fatigue, and upper respiratory tract infection (n = 3 each). Grade 3/4 treatment-related AEs on monotherapy occurred in 1 patient (grade 3 anemia). In the first bortezomib combination cohort, 1 patient had a DLT (elevated amylase). Five monotherapy patients had stable disease, and one combination patient with relapsed/refractory disease had a 26 % reduction of serum M protein at Cycle 2. These results suggest tolerability and potentiated efficacy of bortezomib with HDAC6 inhibitor in relapsed/refractory MM patients.
A number of HDAC inhibitors have been developed and validated through histone hyperacetylation and/or enzymatic HDAC inhibition assays. The majority of these inhibitors non-selectively block HDAC isoforms and trigger significant anti-MM activities. To reduce unfavorable side effects in patients, isoform-selective and/or class-selective HDAC inhibition is under evaluation. For example, a class I inhibitor entinostat and HDAC6-selective inhibitor ACY-1215 demonstrate significant MM cytotoxicity alone and/or in combination with bortezomib, indicating that non-selective HDAC inhibition is not required for this combination treatment.
The other important aspect of HDAC inhibitors is their activity on non-histone protein acetylation, thereby modulating their functions. Indeed, recent advanced technologies of proteomics reveal acetylation of a number of non-histone proteins in cells treated with non-selective HDAC inhibitors. These studies indicate that HDAC inhibitors trigger cell growth inhibition by hyperacetylation not only of histones, but also of MM-relevant non-histone proteins including Hsp90, p53, STAT3, β-catenin, Sp1, c-Myc, Rel-A, PTEN and MDM2. To date, the effect of HDAC isoform-selective inhibitors on these non-histone proteins has not yet been determined.
Recently, compounds have combined two drugs into a single molecule with dual biologic effects. For example, CUDC-101 simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor and human epidermal growth factor receptor 2 in cancer cells and has great potential to improve sensitivity of heterogeneous and/or drug-resistant tumors . Dual (multi)-targeted hybrid compounds, such as combination of proteasome and HDAC inhibitors may also have therapeutic efficacy in MM.
Conflict of interest
The authors do not have conflict of interest.
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