Romidepsin represents a breakthrough in epigenetic cancer therapy as a potent histone deacetylase (HDAC) inhibitor. Originally isolated from Chromobacterium violaceum, this bicyclic depsipeptide compound has demonstrated remarkable efficacy against various malignancies, particularly peripheral T-cell lymphomas (PTCLs). With its unique mechanism of action and proven clinical benefits, romidepsin offers new hope for patients with refractory cancers.
Mechanism of action of Romidepsin
Romidepsin binds to intracellular and intranuclear HDAC. This binding leads to hyperacetylation of histones. As a result, DNA unfolds and becomes more accessible. The increased accessibility of DNA allows transcription factors to bind more easily. This change affects the activity of many genes related to cell growth, proliferation, and apoptosis. Ultimately, these effects lead to cell death in sensitive tumors.
Romidepsin exerts its anticancer effects through potent inhibition of class I HDAC enzymes at nanomolar concentrations. In hepatocellular carcinoma (HCC) cells, romidepsin treatment (0-60 nM, 0-48 hours) induces dose- and time-dependent G2/M cell cycle arrest. The drug simultaneously triggers apoptosis through caspase activation, evidenced by increased cleavage of caspase-3, caspase-9, and PARP proteins. These dual mechanisms make romidepsin particularly effective against rapidly proliferating tumor cells.
Clinical Efficacy of Romidepsin
The drug’s clinical efficacy has been demonstrated in multiple studies. In PTCL patients, romidepsin administration (14 mg/m² intravenously on days 1, 8, and 15 of a 28-day cycle) achieved an overall response rate of 25%, with 15% achieving complete remission. The median duration of response reached 17 months, showcasing its durable therapeutic effects. Importantly, responses were observed across various PTCL subtypes, including angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma.
Preclinical studies reveal romidepsin’s broad anticancer potential beyond hematologic malignancies. In HCC models, the drug (0.5-1 mg/kg, administered intraperitoneally every 3 days for 21 days) significantly inhibited tumor growth while modulating key biomarkers. Treated tumors showed reduced Ki-67 expression and increased apoptotic markers, confirming the drug’s antiproliferative effects in solid tumors.
The favorable safety profile of romidepsin, coupled with its novel mechanism of action, positions it as an ideal candidate for combination therapies. Current research explores synergistic effects with conventional chemotherapeutics and newer targeted agents. Its ability to modify the tumor microenvironment and enhance immune recognition further expands its potential applications in cancer immunotherapy.
Reference
[1] Shustov, Andrei. Therapeutic advances in hematology vol. 4,3 (2013): 173-87.
