What question did this study set out to answer?

The aim is to assess the effectiveness of epigenetic modulating agents in enhancing antitumor responses during hyperthermic intraperitoneal chemotherapy.

April 5, 2026

Abstract 5292: Epigenetic modulators romidepsin and mithramycin A reactivate tumor-suppressive programs and suppress c-MYC under hyperthermic conditions in colorectal peritoneal metastasis

Key Points

The aim is to assess the effectiveness of epigenetic modulating agents in enhancing antitumor responses during hyperthermic intraperitoneal chemotherapy.
Compared effects of romidepsin and mithramycin A to mitomycin C in colorectal cancer cells.
Evaluated cytotoxicity, clonogenic survival, and migration under normothermic and hyperthermic conditions.
Analyzed expressions of tumor suppressor genes and c-MYC via transcriptomic analysis.
Romidepsin and mithramycin A exhibited greater cytotoxicity than mitomycin C.
These agents significantly decreased clonogenic survival and inhibited migration.
Both agents increased p21 and cleaved caspase-3 levels, indicating reactivation of tumor-suppressive programs.
They restored expression of multiple silenced tumor suppressor genes, such as SPRY2 and TIMP3.

Abstract

Abstract Colorectal peritoneal metastasis remains difficult to treat despite advances in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Emerging evidence indicates that epigenetic dysregulation contributes to therapeutic resistance by repressing tumor suppressor pathways and sustaining oncogenic transcriptional programs. To evaluate whether epigenetically active agents improve antitumor responses relevant to HIPEC, we compared the histone deacetylase inhibitor romidepsin (Ro) and the Sp1 transcription factor inhibitor mithramycin A (MA) with the standard HIPEC agent mitomycin C (MMC) in HCT116 and HT29 colorectal cancer cells exposed to normothermic (37°C) or hyperthermic (42°C) conditions for 90 minutes. Both Ro and MA induced greater cytotoxicity, reduced clonogenic survival, and more strongly inhibited migration relative to MMC. Mechanistically, these agents robustly increased p21 and cleaved caspase-3 expression, consistent with reactivation of tumor-suppressive and apoptotic programs, while markedly suppressing c-MYC. Transcriptomic analysis further revealed that Ro and MA restored the expression of multiple epigenetically silenced tumor suppressor genes, including SPRY2, HIC1, TIMP3, and DKK1, indicating broad reversal of transcriptional repression. Hyperthermia variably augmented drug responses in a pathway-dependent manner, suggesting synergistic interactions between heat stress and chromatin remodeling. Ongoing studies using a murine HIPEC model with HCT116 peritoneal xenografts will define the molecular correlates and therapeutic potential of integrating epigenetic modulators into HIPEC-based regimens for colorectal peritoneal metastasis. Citation Format: Yazid Ghanem, Gena Topper, Sahil Jethi, Jessica Collier, Marlena Buonasorte, Yong Ki Hong, Weam Othman Elbezanti. Epigenetic modulators romidepsin and mithramycin A reactivate tumor-suppressive programs and suppress c-MYC under hyperthermic conditions in colorectal peritoneal metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5292.

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