Abstract 2805: Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis

Abstract

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to have effects against colorectal cancer (CRC), since evidence has emerged that people who routinely use NSAIDs show a lower risk of CRC. Among NSAIDs, cyclooxygenase-2 (COX2) inhibitors are thought to exert its anti-cancer effect through blocking prostaglandin (PG) E2 whose actions are mediated by signaling via four receptors EP1, EP2, EP3, and EP4. Previous animal experiments have demonstrated that the development of colon tumor is suppressed by knocking down of either EP1 or EP4. In the present study, we investigate the effect of a novel small molecule EP4 antagonist on rat colon tumorigenesis. Employed animal is Kyoto Apc Delta (KAD) rat which has Apc mutation and is susceptible to chemically-induced CRC. Five-week-old KAD rats received injection of azoxymethane (20 mg/kg i.p.) and 2% dextran sodium sulfate in drinking water for two weeks, and then they were divided into two groups: no treatment (control) group and the group treated with an EP4 antagonist RQ-00015986 (RQ-15986) which was kindly provided by AskAt Inc. RQ-15986-treated 17-week-old KAD rats showed lower colon tumor incidence (37.5% vs 100% in control group, P < 0.05) and smaller multiplicity (1.33 ± 0.58 vs 2.86 ± 0.69 in control group, P < 0.05). The expression levels of inflammatory cytokines, including TNF-alpha and IL-6, in colonic mucosa were decreased in RQ-15986-treated group. By treatment with RQ-15986, the expression levels of monocyte chemo-attractant protein-1 (MCP-1) and indoleamine 2,3-dioxygenase (IDO) were also down-regulated in colon mucosa. Immunohistochemical analyses of colonic membrane revealed that PCNA-labeling index was lower and that F4/80 positive cells were fewer in RQ-15986-treated group. These findings suggest that RQ-15986 may suppress CRC development through mediating immune system and controlling chronic inflammation in the colon. Citation Format: Yohei Shirakami, Hiroyasu Sakai, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki, Masahito Shimizu, Mitsuru Seishima. Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2015-2805