Abstract 4894: Identification of small molecules for the prevention and treatment of colon cancer

Abstract

Abstract Metastatic colon cancer or colorectal cancer (CRC) is associated with poor survival rate which is less than 5% due to chemo resistance. We previously showed that overexpression of AKT and Notch1 are key players for progression of metastasis of colon cancer cells. Withaferin-A (WA) is a potent herbal molecule that inhibited CRC growth by down regulating AKT and Notch1 signaling in both in vitro and in vivo colon cancer models. We found that WA binds to AKT with a predicted binding affinity of -10.6 kcal/mol and inhibited its activation. So, we designed and developed several analogs of WA, that exhibits a stronger AKT binding (binding energy higher than -10 kcal/mole) and more potent than the parental WA. UL16 is one such compound which inhibited the growth of colon cancer cells (HCT-116 and SW-620: IC50-300nM) at nanomolar concentration. Western blot analysis revealed that UL16 inhibits AKT/NF-κβ/ Bcl2- signaling axis in colon cancer cells. In addition, UL16 concurrently inhibited Notch1 signaling pathway in colon cancer cells. Then we systematically investigated the anti-migratory and anti-invasive effect of UL16by cell migration and invasion assays. Inhibition of both migration and invasion of colon cancer cells corresponds with downregulation of mesenchymal markers of Snail, Slug and β-catenin expression. We also examined the in vivo efficacy of UL16 in ApcMin/+ mouse model. Treatment of ApcMin/+ with UL16 (0.5 mg/kg/IP/twice a week) over 12 weeks significantly reduced the number of intestinal polyps (distal 84%; Middle 63% and Proximal 2%) as compared vehicle treated mice. In addition, we also observed 50% reduction in number of colon tumors in UL16 treated mice. Our ongoing immunohistochemistry studies may confirm the in vitro mechanistic results. In conclusion, our studies suggest that UL16 inhibits both AKT and Notch1 signaling and suppresses intestinal polyp formation in ApcMin/+ mice. Hence UL16could be a viable therapeutic agent for treating patients with metastatic colon cancer. Citation Format: Deeksha Pal, Becca Von Baby, Balaji Chandrasekaran, Arun Sharma, Chendil Damodaran. Identification of small molecules for the prevention and treatment of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4894. doi:10.1158/1538-7445.AM2017-4894