Abstract 2604: Chemoprevention of colorectal cancer by LFA-9, a novel dual mPGES-1/5-LOX inhibitor: safer approaches to 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 cardiovascular risk. Mechanistic studies suggest that sparing COX-1/2, prostaglandin (PG)I2 synthase and selectively targeting microsomal PG synthase-1 (mPGES-1) and 5-lipoxygenase (5-LOX) would inhibit PGE2 and Leukotrienes (LTs), respectively. To design and develop selective inhibitors of mPGES-1/5-LOX, we used insilico small molecular docking simulation approaches, and identified LFA-9 as a novel selective dual mPGES-1/5-LOX inhibitor among >20 analogs. Azoxymethane (AOM)-induced rat colonic tumors were utilized to assess inhibitory effects of LFA-9 on mPGES-1 and 5-LOX ex-vivo. At 7.5 μM, LFA-9 inhibited the mPGES-1 and 5-LOX activities by ∼57% and ∼68%, respectively. Maximum tolerable dose (100 -1,600ppm) of LFA-9 in AIN-76A diet on male C57Bl/6 mice were tested and observed that <1,600 ppm dietary LFA-9 to be safe and free from liver, GI and hematological toxicities. In AOM/DSS-induced colonic inflammation in rat, LFA-9 at ≥200ppm abolished the inflammation and suppressed mPGES-1 and 5-LOX activities in a dose-response manner. Potential CRC preventive efficacy of LFA-9 was assessed in AOM-rat carcinogenesis with colonic 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 and two week after the AOM/DSS treatment, LFA-9 (200, 400, and 600ppm) was fed by diet and ACF were evaluated after six-weeks. LFA-9 showed dose-response (P<0.0001) inhibitory effect on ACFs formation. At 600ppm, LFA-9 significantly inhibited colonic total ACF and multi-crypts by >60% (P<0.0001). In APCMin/+ mice study, six-week-old male and female mice (10/group) were fed diet containing 0, 350, and 700 ppm LFA-9 for 14 weeks. Male and female APCMin/+ mice fed control diet developed 58±3.8 (Mean±SEM) and 59±5.9 polyps, respectively. LFA-9 administration at 350 and 700ppm in APCMin/+ mice significantly (p<0.0001) reduced total intestinal tumor multiplicity and size dose-dependently (31.6± 5.9 and 24.3±3.7, male mice; and 26.2±5.6 and 15.5±1.8, female mice, respectively). At the high dose both male and female mice showed a > 80% suppression of polyps with >2mm size. Mice fed 350ppm LFA9 showed colon tumor inhibition of 60% (male) and 90% (female). It is noteworthy that both male and female mice fed 700ppm LFA-9 showed 91% inhibition of colon tumors. LFA-9 showed significant suppression of markers of proliferation and inflammation. Overall, above results suggest LFA-9 as a novel dual mPGES-1/5-LOX inhibitor, a safer agent than other NSAIDs and has a potential for prevention of CRC in high-risk patients. (Grant Support: NCI N01-CN 25001-26). Citation Format: Naveena B. Janakiram, Altaf Mohammed, Gopal Pathuri, Venkateshwar Madka, Rebekah Ritchie, Taylor Bryant, Yuting Zhang, Qian Li, Stan Lightfoot, Hariprasad Gali, Steele E. Vernon, Chen S. Suen, Chinthalapally V. Rao. Chemoprevention of colorectal cancer by LFA-9, a novel dual mPGES-1/5-LOX inhibitor: safer approaches to chemoprevention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2604.