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A focus on the preclinical development and clinical status of the histone deacetylase inhibitor, romidepsin (depsipeptide, Istodax(®)).

ABSTRACT: Romidepsin (Istodax(®), depsipeptide, FR901228, FK228, NSC 630176) is a cyclic peptide, broad-spectrum, potent histone deacetylase inhibitor, with activity mainly against class I histone deacetylase enzymes. In this article, we give an overview of the putative modes of action, such as effects on gene expression, cell cycle regulation, apoptosis induction, DNA repair, protein acetylation and induction of autophagy. Romidepsin has mainly been developed as a therapy for hematologic malignancies and is approved by the US FDA for the treatment of cutaneous T-cell lymphomas. This report outlines the laboratory and clinical development of the compound as a single agent that has more recently been evaluated in combination with other anticancer therapeutics, such as proteasome inhibitors.

SUBMITTER: Harrison SJ

PROVIDER: S-EPMC7457146 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A focus on the preclinical development and clinical status of the histone deacetylase inhibitor, romidepsin (depsipeptide, Istodax(®)).

Harrison Simon J SJ Bishton Mark M Bates Susan E SE Grant Steven S Piekarz Richard L RL Johnstone Ricky W RW Dai Yun Y Lee Becki B Araujo Maria E ME Prince H Miles HM

Epigenomics 20121001 5

Romidepsin (Istodax(®), depsipeptide, FR901228, FK228, NSC 630176) is a cyclic peptide, broad-spectrum, potent histone deacetylase inhibitor, with activity mainly against class I histone deacetylase enzymes. In this article, we give an overview of the putative modes of action, such as effects on gene expression, cell cycle regulation, apoptosis induction, DNA repair, protein acetylation and induction of autophagy. Romidepsin has mainly been developed as a therapy for hematologic malignancies and ...[more]

PMID: 23130838

Similar Datasets

Histone deacetylase inhibitor romidepsin inhibits de novo HIV-1 infections.

Project description:Adjunct therapy with the histone deacetylase inhibitor (HDACi) romidepsin increases plasma viremia in HIV patients on combination antiretroviral therapy (cART). However, a potential concern is that reversing HIV latency with an HDACi may reactivate the virus in anatomical compartments with suboptimal cART concentrations, leading to de novo infection of susceptible cells in these sites. We tested physiologically relevant romidepsin concentrations known to reactivate latent HIV in order to definitively address this concern. We found that romidepsin significantly inhibited HIV infection in peripheral blood mononuclear cells and CD4(+) T cells but not in monocyte-derived macrophages. In addition, romidepsin impaired HIV spreading in CD4(+) T cell cultures. When we evaluated the impact of romidepsin on quantitative viral outgrowth assays with primary resting CD4(+) T cells, we found that resting CD4(+) T cells exposed to romidepsin exhibited reduced proliferation and viability. This significantly lowered assay sensitivity when measuring the efficacy of romidepsin as an HIV latency reversal agent. Altogether, our data indicate that romidepsin-based HIV eradication strategies are unlikely to reseed a latent T cell reservoir, even under suboptimal cART conditions, because romidepsin profoundly restricts de novo HIV infections.

| S-EPMC4468708 | biostudies-other

Use of class I histone deacetylase inhibitor romidepsin in combination regimens.

Project description:Histone deacetylase (HDAC) inhibitors are epigenetic-modifying agents that have shown promise as anticancer therapies. Several HDAC inhibitors have been approved by the US Food and Drug Administration (FDA) as single-agent therapies to treat T-cell lymphoma. The synergistic combination of HDAC inhibitors with other anticancer agents has the potential to constitute treatment regimens with enhanced efficacy. Romidepsin is a structurally unique, potent, bicyclic class 1 selective HDAC inhibitor approved by the FDA for the treatment of patients with peripheral T-cell lymphoma who have had at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have had at least 1 prior systemic therapy. Here, we review data that support the use of romidepsin in combination with other anticancer agents for the treatment of various malignancies. Promising results have emerged from early clinical studies, supporting the potential for romidepsin combination regimens to constitute safe and effective treatments for cancer.

| S-EPMC4950458 | biostudies-literature

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis.

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects.

| S-EPMC5564721 | biostudies-other

The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients.

Project description:Romidepsin is the second histone deacetylase inhibitor (HDACi) approved for the treatment of advanced stages of cutaneous T-cell lymphoma (CTCL). Recent in vitro data suggest that HDACis suppress immune function although these findings have not been confirmed in patients. Thus, we serially examined the cellular immune function of eight CTCL patients undergoing treatment with three cycles of romidepsin. We measured the patients' natural killer (NK) and dendritic cell (DC) function and performed an in vitro terminal deoxynucleotidyl transferase dUTP nick end labeling assay to measure cellular apoptosis. Patients' NK cell cytolytic activity decreased from baseline to the third cycle of treatment (P = 0.018) but stimulation with a toll-like receptor (TLR) agonist increased this activity (P = 0.018). At baseline, a TLR agonist could both activate patients' DC (P = 0.043) and stimulate interleukin-12 protein production (P = 0.043) but both were suppressed after the first cycle of romidepsin. Finally, we observed increased specificity for romidepsin-induced CD4+ tumor cell apoptosis and dose-dependent increases in cellular apoptosis of healthy cells in multiple lineages (P < 0.05). These findings raise concern that HDACis suppress immune function in CTCL patients and they support the concurrent use of multiple immune stimulatory agents to preserve the host immune response.

| S-EPMC3638752 | biostudies-literature

Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin.

Project description:The Chromobacterium sp. Panama bacterium has in vivo and in vitro anti-Plasmodium properties. To assess the nature of the Chromobacterium-produced anti-Plasmodium factors, chemical partition was conducted by bioassay-guided fractionation where different fractions were assayed for activity against asexual stages of P. falciparum. The isolated compounds were further partitioned by reversed-phase FPLC followed by size-exclusion chromatography; high resolution UPLC and ESI/MS data were then collected and revealed that the most active fraction contained a cyclic depsipeptide, which was identified as romidepsin. A pure sample of this FDA-approved HDAC inhibitor allowed us to independently verify this finding, and establish that romidepsin also has potent effect against mosquito stages of the parasite's life cycle. Genomic comparisons between C. sp. Panama and multiple species within the Chromobacterium genus further demonstrated a correlation between presence of the gene cluster responsible for romidepsin production and effective antiplasmodial activity. A romidepsin-null Chromobacterium spp. mutant loses its anti-Plasmodium properties by losing the ability to inhibit P. falciparum HDAC activity, and romidepsin is active against resistant parasites to commonly deployed antimalarials. This independent mode of action substantiates exploring a chromobacteria-based approach for malaria transmission-blocking.

| S-EPMC5906607 | biostudies-literature

Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma.

Project description:BackgroundEpigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histone deacetylases (HDACs) induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby uncoiling condensed chromatin favoring transcription of silenced genes, including tumor suppressor genes. Romidepsin is an HDAC inhibitor that exhibits antiproliferative and apoptotic effects against multiple myeloma cell lines.MethodsA phase 2 trial was performed of romidepsin in patients with multiple myeloma who were refractory to standard therapy. Treatment was comprised of romidepsin (13 mg/m²) given as a 4-hour intravenous infusion on Days 1, 8, and 15 every 28 days). Thirteen patients received a median of 2 cycles of therapy (range, 1-7 cycles).ResultsAlthough no patients had an objective response, 4 of 12 patients with secretory myeloma exhibited evidence of M-protein stabilization, and several other patients experienced improvement in bone pain and resolution of hypercalcemia.ConclusionsThe results of the current study demonstrate that romidepsin, as a single agent, is unlikely to be associated with a response rate of ≥30% in patients with refractory myeloma, although there was some clinical evidence suggesting a biological effect associated with therapy.

| S-EPMC3010462 | biostudies-literature

Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both CpG and H3K9 methylation on the promoter.

Project description:Histone deacetylase inhibitor (HDACi) has been shown to demethylate the mammalian genome, which further strengthens the concept that DNA methylation and histone modifications interact in regulation of gene expression. Here, we report that an HDAC inhibitor, depsipeptide, exhibited significant demethylating activity on the promoters of several genes, including p16, SALL3, and GATA4 in human lung cancer cell lines H719 and H23, colon cancer cell line HT-29, and pancreatic cancer cell line PANC1. Although expression of DNA methyltransferase 1 (DNMT1) was not affected by depsipeptide, a decrease in binding of DNMT1 to the promoter of these genes played a dominant role in depsipeptide-induced demethylation and reactivation. Depsipeptide also suppressed expression of histone methyltransferases G9A and SUV39H1, which in turn resulted in a decrease of di- and trimethylated H3K9 around these genes' promoter. Furthermore, both loading of heterochromatin-associated protein 1 (HP1alpha and HP1beta) to methylated H3K9 and binding of DNMT1 to these genes' promoter were significantly reduced in depsipeptide-treated cells. Similar DNA demethylation was induced by another HDAC inhibitor, apicidin, but not by trichostatin A. Our data describe a novel mechanism of HDACi-mediated DNA demethylation via suppression of histone methyltransferases and reduced recruitment of HP1 and DNMT1 to the genes' promoter.

| S-EPMC2423178 | biostudies-literature

MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor.

Project description:To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials.

| S-EPMC3656450 | biostudies-literature

Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer.

Project description:ObjectivesPatients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors.MethodsA phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m(2) as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks.ResultsObjective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21(Waf1/Cip1) characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors.ConclusionsSingle agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

| S-EPMC3465519 | biostudies-literature

Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors.

Project description:Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I-selective HDAC inhibitor, OKI-179. OKI-179 and its cell active predecessor OKI-005 are thioester prodrugs of the active metabolite OKI-006, a unique congener of the natural product HDAC inhibitor largazole. OKI-006, OKI-005, and subsequently OKI-179, were developed through a lead candidate optimization program designed to enhance physiochemical properties without eroding potency and selectivity relative to largazole. OKI-005 displays antiproliferative activity in vitro with induction of apoptosis and increased histone acetylation, consistent with target engagement. OKI-179 showed antitumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies.

| S-EPMC9600708 | biostudies-literature

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