Abstract 5243: Novel non-COX inhibitory sulindac derivative with β-catenin suppressing activity reduces the formation of colorectal adenomas and adenocarcinomas in the APC +/min-FCCC mouse model

Sulindac can reduce the number and size of precancerous colonic adenomas in patients with familial adenomatous polyposis (FAP), but is not recommended for long-term use as a cancer chemopreventive drug because of potentially fatal toxicities associated with cyclooxygenase (COX) inhibition. Here we characterize the antineoplastic properties of a novel sulindac derivative, ADT-061, that lacks COX-1 and COX-2 inhibitory activity. ADT-061 potently and selectively inhibited colon tumor cell growth in vitro with IC50 values of 0.3-0.5 μM by inducing apoptosis without affecting the growth of normal colonocytes at concentrations 100x higher. By comparison, sulindac sulfide (SS) inhibited colon tumor cell growth with IC50 values of 40-60 μM, and had only modest tumor cell selectivity. While SS non-selectively inhibits multiple cyclic GMP phosphodiesteraes (PDE) isozymes, previous studies have suggested an important role for PDE10 in colon cancer (Li et al, Oncogene, 2014; Lee et al, Oncotarget, 2015). At concentrations comparable to its IC50 values, ADT-061 selectively inhibits PDE10 to induce an increase in intracellular cGMP levels and activate protein kinase G (PKG). ADT-061 also suppressed nuclear levels of β-catenin and induced cell cycle arrest and apoptosis, within the same concentration range that inhibits tumor cell growth. With attractive drug-like properties, the chemopreventive activity ADT-061was assessed using the APC+/min-FCCC mouse model of spontaneous colorectal tumorigenesis. Prior to treatment, colonoscopy exams were performed on all APC+/min-FCCC mice (males, 6-7 weeks of age) to ensure the absence of colorectal adenomas. At 7-8 weeks of age, mice were assigned (19 per group) to receive either unsupplemented chow (control) or chow supplemented with ADT-061 (1500ppm) for 14 weeks. No discernible toxicity was observed during the experimental period. Double-blinded pathological analysis of fixed colon tissues revealed that ADT-061 not only reduced the multiplicity of colonic adenomas by 50% (Mean ± SEM, control vs. ADT-061, 3.95 ± 0.81 vs. 1.95 ± 0.58, P < 0.05), but also decreased the incidence of colonic adenomas by 36.7% (control vs. ADT-061, 94.7% vs. 57.9%, respectively). ADT-061 treatment reduced the multiplicity of polypoid adenomas (36%), flat adenomas (100%, P < 0.05), and microadenomas (69%). The formation of colonic adenocarcinomas found in 15.8% of untreated mice was completely inhibited in mice treated with ADT-061. These data indicate