Romidepsin is a potent bicyclic depsipeptide and a selective inhibitor of histone deacetylases (HDACs), specifically Class I HDACs (1, 2) and Class IIb (HDAC6). It was originally isolated from the fermentation broth of the Gram-negative bacterium Chromobacterium violaceum. Its discovery stemmed from screening for agents that could reverse transformed morphology in oncogene-expressed cells, highlighting its potential as an anti-cancer agent. Romidepsin is a prodrug; its disulfide bond is reduced intracellularly to release a zinc-binding thiol that inhibits HDAC activity, leading to histone hyperacetylation, altered gene expression, cell cycle arrest, and apoptosis in malignant cells. It holds significant clinical importance as an FDA-approved chemotherapeutic agent for the treatment of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), representing a cornerstone in epigenetic cancer therapy.
Quick Facts
| Also Known As | FK228, FR901228, Depsipeptide |
|---|---|
| Sequence | Cyclo-(D-Val-D-Cys-D-aThr-L-Val-D-Cys-L-aThr-D-Val-L-Cys-D-aThr-L-Val-L-Cys-L-aThr) |
| Molecular Formula | C24H36N4O6S2 |
| Molecular Weight | 540.7 Da |
| PubChem CID | 5352062 |
Research Parameters
| Half-Life | ~3 hours (terminal half-life after IV administration) |
|---|---|
| Stability | Lyophilized powder is stable under recommended storage conditions. The reconstituted solution in supplied diluent is stable for at least 24 hours at room temperature or up to 7 days under refrigeration (2-8°C). |
| Solubility | Supplied as a lyophilized powder. Reconstituted first with provided diluent (80% propylene glycol, 20% dehydrated alcohol), then further diluted in 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. |
| Vial Size | 10 mg |
| Storage (Lyophilized) | Store at 2-8°C (36-46°F). Retain in original package to protect from light. |
| Storage (Reconstituted) | After final dilution in infusion bag, may be stored at room temperature for up to 24 hours or refrigerated at 2-8°C (36-46°F) for up to 7 days. |
| Typical Research Dose | 14 mg/m2 (approximately 280-350 mcg/kg, depending on body surface area) |
| Cycle Parameters | Administered as a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Treatment continues until disease progression or unacceptable toxicity. |
| Amino Acid Count | 25 |
Mechanism of Action
Romidepsin is a prodrug that exerts its primary therapeutic effects through potent inhibition of histone deacetylase (HDAC) enzymes, leading to epigenetic modulation of gene expression and multiple downstream cellular effects. Its mechanism involves several key pathways.
HDAC Inhibition and Epigenetic Modulation: Following cellular uptake, romidepsin's disulfide bond is reduced by glutathione, releasing a free thiol that acts as a zinc-chelating warhead. This active form binds to the zinc ion in the catalytic pocket of Class I HDACs (HDAC1, HDAC2) and Class IIb HDAC6, inhibiting their deacetylase activity. This results in the accumulation of acetylated histones (e.g., H3, H4) and non-histone proteins, altering chromatin structure and gene transcription.
Cell Cycle Arrest and Apoptosis: Hyperacetylation leads to transcriptional activation of genes involved in cell cycle regulation, such as p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor. Upregulation of p21 induces G1 and/or G2/M phase cell cycle arrest. Concurrently, romidepsin modulates the expression of pro-apoptotic (e.g., BAX, BIM) and anti-apoptotic (e.g., BCL-2) proteins, inducing intrinsic mitochondrial apoptosis.
Oxidative Stress and DNA Damage: Romidepsin treatment generates reactive oxygen species (ROS) within cancer cells. This oxidative stress contributes to DNA damage, further activating DNA damage response pathways and enhancing apoptotic signaling.
Immunomodulatory Effects: By modulating the acetylation of transcription factors and other proteins, romidepsin can affect the expression of cytokines and surface antigens, potentially enhancing tumor immunogenicity and affecting immune cell function.
Research Applications
Oncology: Romidepsin is extensively researched in hematological and solid malignancies. Beyond its approved use in T-cell lymphomas, clinical and preclinical studies investigate its efficacy against various cancers, including acute myeloid leukemia, multiple myeloma, and prostate cancer. Research focuses on its ability to induce differentiation, apoptosis, and sensitize resistant cancer cells to other therapies.
Virology and Latency Reversal: A significant area of investigation is romidepsin's potential as a latency-reversing agent (LRA) for HIV-1 eradication strategies. By inhibiting HDACs, it can reactivate latent HIV-1 provirus in resting CD4+ T-cells, making the infected cells visible to the immune system or susceptible to antiviral drugs, a concept termed 'shock and kill'.
Autoimmune and Inflammatory Diseases: Preliminary research explores HDAC inhibition in modulating immune responses. By altering the expression of inflammatory genes and regulatory T-cell function, romidepsin and similar compounds are studied in models of autoimmune diseases like lupus and rheumatoid arthritis for their potential immunosuppressive effects.
Safety & Side Effects
The safety profile is primarily defined by clinical trials. Common adverse effects include nausea, fatigue, anorexia, thrombocytopenia, neutropenia, and anemia. Electrocardiogram abnormalities, including T-wave and ST-segment changes, are frequently observed. A serious but manageable side effect is the potential for serious infections due to myelosuppression. Theoretical concerns include cardiac toxicity (QTc prolongation) and tumor lysis syndrome. Animal toxicology studies have shown dose-dependent hematological and gastrointestinal toxicity.
Dosage Information
This information is derived from clinical research protocols and is presented for educational purposes only. In clinical oncology, romidepsin is administered intravenously. The FDA-approved dosing regimen for CTCL and PTCL is 14 mg/m2 administered as a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Dose adjustments are made based on toxicity. Research into alternative schedules and combinations with other chemotherapeutic agents is ongoing.
References
Piekarz, R.L. et al. 'Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma.' Journal of Clinical Oncology, 2009.
Whittaker, S.J. et al. 'Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.' Journal of Clinical Oncology, 2010.
Coiffier, B. et al. 'Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy.' Journal of Clinical Oncology, 2012.
Archin, N.M. et al. 'Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.' Nature, 2012. (Seminal study on HDACi for HIV latency).
Saito, A. et al. 'A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors.' Proceedings of the National Academy of Sciences, 1999. (Early foundational work on HDACi).
Ueda, H. et al. 'FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity.' The Journal of Antibiotics, 1994. (Original isolation and characterization).