Abstract LB-172: Novel mechanistic insight into the prevention and treatment of colorectal cancer and familial adenomatous polyposis by anthocyanidins
Authors: Mudd Ashley M. , Gu Tao , Jeyabalan Jeyaprakash , Munagala Radha , Egilmez Nejat K. , Gupta Ramesh C. 
Published: August 2018

Abstract
Familial adenomatous polyposis (FAP) is an inherited disorder caused by mutations in the adenomatous polyposis coli (APC) gene. If left untreated, nearly 100% of patients with FAP will eventually develop colorectal cancer, which is the third most common form of cancer diagnosed in men and women and the third leading class for cancer-related deaths within the United States. Given the prevalence of colon cancer both in the United States and worldwide, further insight into developing novel and more effective prevention and treatment strategies are warranted. The family of plant pigments known as the anthocyanins has been identified with a variety of health benefits including chemopreventive as well as therapeutic effects. However, a limitation to current clinical applications of anthocyanins is the high doses that are required. In order to elucidate the chemo-preventive/therapeutic potential and mechanism of action for the active moiety, anthocyanidins (Anthos), a series of in vitro and in vivo experiments were undertaken. The antiproliferative effects of Anthos native mixture isolated from bilberry, as well as individual Anthos and anthocyanins against APC mutant (HT-29), APC wild-type (HCT116) colon cancer cells and CCD-18Co normal colon cells were assessed using an MTT assay. To assess chemopreventive effects, the impact of the Anthos on polyp number was investigated in the APCMin/+ mouse model for FAP. Therapeutic efficacy of Anthos treatment on colorectal tumor number was assessed using an APCMin/+ ETBF mouse tumor model. Mechanistic studies were undertaken to assess the impact of Anthos on Src and EGFR phosphorylation and modulation of downstream targets such as STAT1, STAT3, STAT5, COX-2, p21, Cyclin D1, Cyclin D2 by western blot analysis using cell lysates of colon adjacent normal and tumor tissue from control and Anthos treated animals. Antiproliferation studies showed that the anthocyanidin, delphinidin, yielded greater potency compared to the anthocyanin, delphinidin-3,5-diglucoside against HCT-116 colon cancer cells. Treatment with native Anthos mixture yielded selective antiproliferative activity against colon cancer over normal colon cells. Furthermore, Anthos treatment led to significant reductions in polyp and tumor counts in vivo. Reduced Src and EGFR phosphorylation was observed in Anthos-treated tissue samples, with correlating favorable modulation of downstream targets including STAT1, STAT3, STAT5, COX-2, p21, Cyclin D1, and Cyclin D2. Overall, these results provide a promising outlook on the future of berry Anthos for treatment and prevention of both FAP and CRC. Additionally, results from this study provide highly novel mechanistic insight into the chemopreventive and therapeutic activities of Anthos. Translation of these findings to the clinical setting is one of the main goals moving forward with this research.
Citation Format: Ashley M. Mudd, Tao Gu, Jeyaprakash Jeyabalan, Radha Munagala, Nejat K. Egilmez, Ramesh C. Gupta. Novel mechanistic insight into the prevention and treatment of colorectal cancer and familial adenomatous polyposis by anthocyanidins [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 LB-172.