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.

Targeting Selective Autophagy of Insoluble Protein Aggregates

“…The main indication for HDAC inhibitors is cancer [73,74] but other clinical indications are supported by preclinical evidence [75]. Vorinostat/Zolinza ® [76] and romidepsin/Istodax ® [77] (respectively the hydroxamate SAHA-5.19 and the cyclic depsipeptide FK228-5.20, Figure 5.5) are broad spectrum HDAC inhibitors, acting on all HDAC isoforms. They are both approved for the treatment of cutaneous T-cell lymphoma [78], and romidepsin also for the treatment of peripheral T-cell lymphoma [79].…”

Is Glioblastoma an Epigenetic Malignancy?

“…, inhibitors of DNA methyltransferase (5-azacytidin and decitabin) were approved by the Food and Drug Administration (FDA) in the treatment of myelodysplastic syndrome and a few inhibitors of histone acetylases (vorinostat, romidepsin and panobinostat) are approved in the treatment of hematological malignancies, particularly in refractory or relapsed cutaneous T-cell lymphoma. Other compounds are presently in phase II and III clinical trials [102,103]. Hypomethylating agents are also one of the few epigenetic therapies that have gained FDA approval for routine clinical use.…”

Targeting the Epigenome in Lung Cancer: Expanding Approaches to Epigenetic Therapy

“…To date, histone deacetylation and DNA methylation have been successfully targeted in the clinic. Several epigenetic modifiers have received FDA approval: DNMT inhibitors, decitabine, and 5-azacitidine are approved for treatment of myelodysplastic syndromes (68, 69) and HDAC inhibitors romidepsin and vorinostat are approved for T-cell lymphoma (70–72). …”

“…The major adverse effects of HDAC inhibitors are fatigue, nausea, and vomiting. Most of the agents cause thrombocytopenia, lymphopenia, neutropenia, and electrocardiographic changes including ST and T wave flattening and QT prolongation (72, 73). Selective HDAC inhibition may provide greater efficacy and a wider therapeutic window by reducing adverse effects.…”