Abstract B42: Safer approaches to colorectal cancer chemoprevention

Abstract

Abstract Colorectal cancer (CRC) protective effects of NSAIDs and COX-2 inhibitors are well established; however, they are associated with gastrointestinal (GI) bleeding and enhanced cardiovascular risk. Mechanistic studies suggest that upregulation of 15-PGDH, sparing COX-1/2 and prostaglandin (PG)I2 synthase and/or selectively targeting mPGES-1 and 5-LOX, would reduce the cardiovascular side effects and may improve the chemopreventive efficacy. One unexplored area in colorectal cancer chemoprevention towards safer drug development is limited or no studies on targeting mPGES-1/5LOX. To design and develop selective inhibitors of dual mPGES-1/5-LOX, we used in silico small-molecular docking simulations approaches, and identified LFA-9 as a novel dual mPGES-1/5-LOX inhibitor among >35 analogs. Azoxymethane (AOM)-induced rat colonic tumors were utilized to assess pharmacodynamic inhibitory effects of LFA-9 on mPGES-1 and 5-LOX by Radio-HPLC. At low μM LFA-9 inhibited the mPGES-1 and 5-LOX activities by ~57% and ~68%, respectively. We tested five different doses (100-1,600 ppm) of LFA-9 by modified AIN-76A diet on male C57 mice and observed that <1,600 ppm dietary LFA-9 was found to be safer and free from the liver and GI toxicities. In AOM/DSS-induced colonic inflammation in F344 rat, 200 ppm and above LFA-9 completely abolishes the colonic inflammation and suppresses mPGES-1 and 5-LOX in dose-response manner. Potential CRC preventive efficacy of LFA-9 was assessed AOM-rat carcinogenesis (Aberrant Crypt Foci, (ACF) as surrogate marker in male F344 rats and intestinal tumor inhibition in APCMin/+ mice. In rats, colonic ACF were induced by AOM/DSS treatment, dietary LFA-9 (200, 400, and 600 ppm) showed dose-response (P<0.0001) inhibitory effects on ACFs formation. In APCMin/+ mice study, diet containing 0, 350, and 700 ppm LFA-9 for 14 weeks administration significantly (p<0.0001) reduced total intestinal tumor multiplicity and size dose-dependently in both male and female mice. At high dose both male and female mice showed > 80% suppression of colonic polyps with >2 mm size. Importantly, mice fed with 350-ppm LFA9 showed colon tumor inhibition of 60% (male) and 90% (female). It is noteworthy that both male and female mice fed with 700-ppm LFA-9 showed 91% inhibition of colon tumors. Overall, the above results show that LFA-9 is a novel dual mPGES-1/5-LOX inhibitor, a safer agent and potential for prevention of CRC in high-risk patients. (Grant support: NCI N01-CN 25001-26 and 1R01CA213987-01.) Citation Format: Chinthalapally V. Rao, Altaf Mohammed, Naveena B. Janakiram. Safer approaches to colorectal cancer chemoprevention [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B42.