epz-6438 and regorafenib

Although the survival rate of patients with cancer have increased due to the use of current chemotherapeutic agents, adverse effects of cancer therapy remain a concern. The reversal of drug resistance, reduction in harmful side effects and accelerated increase in efficiency have often been addressed in the development of combination therapeutics. Tazemetostat (EPZ-6438), a histone methyltransferase EZH2 selective inhibitor, was approved by the FDA for the treatment of advanced epithelioid sarcoma. However, the effect of tazemetostat on colorectal cancer (CRC) and 5-FU sensitivity remains unclear. In this study, the enhancement of tazemetostat on 5-FU sensitivity was examined in CRC cells. Our findings demonstrated that tazemetostat combined with 5-FU exhibits synergistic antitumor function in vitro and in vivo in CRC cells. In addition, tazemetostat promotes PUMA induction through the ROS/ER stress/CHOP axis. PUMA depletion attenuates the antitumor effect of the combination therapy. Therefore, tazemetostat may be a novel treatment to improve the sensitivity of tumors to 5-FU in CRC therapy. In conclusion, the combination of 5-FU and tazemetostat shows high therapeutic possibility with reduced unfavorable effects.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Benzamides; Biphenyl Compounds; Cell Line, Tumor; Colorectal Neoplasms; Endoplasmic Reticulum Stress; Enhancer of Zeste Homolog 2 Protein; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Mice, Inbred BALB C; Mice, Nude; Morpholines; Phenylurea Compounds; Proto-Oncogene Proteins; Pyridines; Pyridones; Reactive Oxygen Species; Transcription Factor CHOP; Tumor Suppressor Protein p53; Up-Regulation; Xenograft Model Antitumor Assays