E347: Use of Novel Epigenetic Therapy Agent Romidepsin in Cytoreductive Surgery for Peritoneal Colorectal Cancer

There is on-going debate regarding role of HIPEC benefit for peritoneal carcinomatosis of colon cancer based on efficacy concerns of perfusional agent and ultimately warrants a need for novel therapeutic agent.  Herein, we aim to demonstrate efficacy of FDA-approved epigenetic drugs in comparison to Mitomycin C as perfusional agent during cytoreductive surgery.

Methods:

HCT116, human colon cancer cells, were treated with epigenetic drugs: Romidepsin (selective HDAC inhibitor), Vorinostat (pan-HDAC inhibitor), Mithramycin A (antineoplastic antibiotic with epigenetic effects), Decitabine (DNMT inhibitor), and Tazemetostat (EZH2 inhibitor) compared to Mitomycin C.  The following doses were tested for all drugs: 100 nM, 500 nM, 1 µM, 2.5 µM, 5 µM, 10 µM, 20 µM. The cells were treated with the agents for 90 minutes at 37 °C.  MTT Viability Assay was performed at 48hr and 72hrs post-treatment. qPCR was performed to assess gene expression immediately after 90 minutes of treatment.

Results:

Romidepsin’s IC50 was significantly lower than all the other agents (207nM, p < 0.05). IC50 values for the remaining agents were: Mithramycin A (685 nM), Mitomycin C (1.55 µM), Vorinostat (2.66 µM), Decitabine (7.34 µM), and Tazemetostat (13.46 µM). Romidepsin’s MTT cell viability assay (Figure 1) compares cell viability between the drugs tested at 48 hours. Additionally, further viability testing at 72hr revealed similar results. Finally, using qPCR, we also found that Romidepsin, even at 100nM, enhanced the expression of P53 six-fold, and P21 two-fold compared to untreated cells. This was checked immediately after 90 minutes of treatment.

Conclusions:

We demonstrate a novel epigenetic agent, Romidepsin, with potent anti-proliferative effect on colon cancer cells and warrants further investigation for clinical application for local perfusion during cytoreductive surgery. The additional gene remodeling of the epigenetic agent may provide improved recurrence rates.