Abstract 3097: Chemo prevention effect of Withaferin A, a natural compound, on mouse models of colorectal carcinogenesis

Abstract

Abstract Introduction: Colorectal cancer (CRC) is the most common cancer and one of the leading causes of cancer-related deaths in United States as well as worldwide. Development of sporadic CRC takes an average of 15-20 years, so establishing preventive measures are possible. We are interested in a dietary compound, Withaferin-A (WA), which possesses both chemotherapeutic and chemopreventive properties. WA's effect was studied on both colitis-mediated colon and spontaneous-intestinal carcinogenesis mouse models. Methods: In the present study, two animal models of colon cancer were used to study the chemo- preventive effect of WA. In intestinal tumorigenesis model C57BL/6-ApcMin/+ , mice at six weeks of age were orally fed with the vehicle or WA (4mg/kg body weight of mice) for five days per week for 12-14 weeks. The other model used was AOM/DSS (Azoxymethane/dextran sulfate sodium), which induces gut inflammation and tumorigenesis. Intraperitoneal injection of AOM (8mg/kg) was followed by three cycles of DSS. WA (3mg/kg body weight of mice) was administered five times per week for 8-10 weeks. After completion of the studies, the tumor tissues were subjected to histopathological and molecular analysis. An unpaired Student's t-test was used for statistical analysis. Results: Oral administration of WA to ApcMin/+ mice leads to a significant decrease in the number of intestinal polyps and colon tumors (colon: 42%, p=0.025), proximal: 53%, p=0.0063, middle: 27.84%, p= 0.28, distal: 32.8, p= 0.001) when compared to vehicle-treated mice. Similarly, in AOM/DSS, oral administration of WA reduced polyp multiplicity by 40% (p= 0.02) compared to vehicle-treated controls. Moreover, the treatment group of both colon cancer models showed inhibition of pro-survival signaling markers (Notch1, pAKT and NFκB) as well as a decrease in proliferative markers. Conclusion: Our results suggest that WA effectively suppresses intestinal polyp development and colitis-mediated colon carcinogenesis, suggesting a preventive and therapeutic role in colon cancer models. These findings warrant further investigation to develop novel strategies to achieve maximum benefit of dietary agents for cancer chemoprevention. Citation Format: Deeksha Pal, Balaji Chandrasekaran, Becca Von Baby, Houda Alatassi, Murali Ankem, Chendil Damodaran. Chemo prevention effect of Withaferin A, a natural compound, on mouse models of colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3097.