Chemoprevention of intestinal tumorigenesis by the natural dietary flavonoid myricetin in<i>APCMin/+</i>mice

Abstract

// Ye Li 1, * , Shu-Xiang Cui 2, * , Shi-Yue Sun 3 , Wen-Na Shi 3 , Zhi-Yu Song 3 , Shu-Qing Wang 3 , Xin-Feng Yu 3 , Zu-Hua Gao 4 , Xian-Jun Qu 3 1 Department of Pharmacology, School of Chemical Biology &amp; Pharmaceutical Sciences, Capital Medical University, Beijing, China 2 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China 3 Department of Pharmacology, Capital Medical University School of Basic Medical Sciences, Beijing, China 4 Department of Pathology, McGill University, Montreal, Quebec, Canada * These authors have contributed equally to this work Correspondence to: Xian-Jun Qu, email: quxj@ccmu.edu.cn Zu-Hua Gao, email: zu-hua.gao@mcgill.ca Keywords: myricetin, APC Min/+ mouse model, intestinal adenomatous polyps, Wnt/&beta;-catenin pathway, chronic inflammation Received: December 22, 2015&emsp;&emsp;&emsp;&emsp; Accepted: July 26, 2016&emsp;&emsp;&emsp;&emsp; Published: August 06, 2016 ABSTRACT Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia ( APC Min/+ ) mice. Myricetin was given orally once a day for 12 consecutive weeks. APC Min/+ mice fed with myricetin developed fewer and smaller polyps without any adverse effects. Histopathological analysis showed a decreased number of dysplastic cells and degree of dysplasia in each polyp. Immunohistochemical and western blot analysis revealed that myricetin selectively inhibits cell proliferation and induces apoptosis in adenomatous polyps. The effects of myricetin were associated with a modulation the GSK-3&beta; and Wnt/&beta;-catenin pathways. ELISA analysis showed a reduced concentration of pro-inflammatory cytokines IL-6 and PGE2 in blood, which were elevated in APC Min/+ mice. The effect of myricetin treatment was more prominent in the adenomatous polyps originating in the colon. Further studies showed that myricetin downregulates the phosphorylated p38 MAPK/Akt/mTOR signaling pathways, which may be the mechanisms for the inhibition of adenomatous polyps by myricetin. Taken together, our data show that myricetin inhibits intestinal tumorigenesis through a collection of biological activities. Given these results, we suggest that myricetin could be used preventatively to reduce the risk of developing colon cancers.