Abstract 4734: Response of bladder and colon cancer cells to combined treatment with bromodomain and histone deacetylase inhibitors

Abstract

Since bromodomains of proteins bind acetylated histone lysine side chains while histone deacetylase inhibitors increase the level of histone acetylation, it seemed possible that bromodomain inhibitors might counteract some cellular responses to the action of histone deacetylase inhibitors. We have examined this possibility in bladder and colon cancer cells treated with combinations of bromodomain and histone deacetyalase inhibitors. Actions on growth and on the induction of alkaline phosphatase activity by histone deacetylase inhibitors were investigated. Compounds studied were the bromodomain inhibitors JQ1, I-BET763, olinone and RVX208 and the histone deacetylase inhibitors butyrate, RGFP966 and valproate. The cells studied were ones in which alkaline phosphatase activity is induced by histone deacetylase inhibitors. They were bladder cancer lines 5637, HT1197 and HT1376 and colon cancer lines Caco-2 and HT29. The combination that most clearly showed decreased induction of alkaline phosphatase activity by a bromodomain inhibitor was butyrate plus JQ1. If this action represents blocking combination of bromodomain-containing transcription factors with acetylated histones one might anticipate that inhibitory effects of histone deacetylase inhibitors on growth might be mitigated by combination with bromodomain inhibitors. However, the tendency was for additive effects on growth inhibition in accord with some data in the literature. Of the bromodomain inhibitors that were studied, JQ1 was the most effective as a growth inhibitor and olinone was the least effective. The mechanism for additive effects of bromodomain and histone deacetylase inhibitors on growth remains to be defined but antagonistic effects on cell differentiation appear possible. Citation Format: Michael A. Lea, Niyati Patel, Charles desBordes. Response of bladder and colon cancer cells to combined treatment with bromodomain and histone deacetylase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4734.