Effects Of Chinese Bayberry Phenolic Compounds On Antioxidant And Anticancer

Chinese bayberry (Myrica rubra Sieb.et Zucc) is one of the main fruits in Zhejiang province and an important part of human diet fruits. Previous works indicated that Chinese bayberry contains phenolics such as phenolic acids, anthocyanin and flavonoids. The results from recent studies found that phenolics have antioxidant activities. At present, the antioxidant models always combined solvent extraction with chemical antioxidant assays. However, it is not in accordance with physiological conditions when using the traditional antioxidant models. Therefore, we developed a new antioxidant model which is combined in vitro digestion and cellular antioxidant assay to evaluate the antioxidant activities of Chinese bayberry. Additionaly, the antioxidant activity is always accompanied by antiproliferative activity of cancer cells. Due to a lack of screening biomarkers, most cancers are diagnosed at late stages. Platinum drugs, such as cisplatin and its analogues, are the most frequently used agents for the treatment of human cancer. However, these agents have apparent drawbacks including unacceptable rates of normal cell toxicity and cancer cell resistance to conventional platinum-based chemotherapy. So this paper determined the antiproliferative activity of Chinese bayberry phenolic compounds and studied its mechanisms behind this inhibitory effects. The main contents and results are as follows:1. The phenolic profiles in solvent extracts and in vitro digesta of four kinds of Chinese bayberry were compared. The total phenolic contents and total anthocyanin contents in the solvent extractis were more than in vitro digesta. However the free phenolic acids in in vitro digesta were more than solvent extractis.2. Antioxidant activity assays, including ABTS, FRAP, DPPH, ORAC and CAA, were compared. Digesta had lower ABTS, FRAP and DPPH values but higher CAA values than extracts. By analyzed, FPA were higher correlated with the chemical antioxidant assays in digesta. The correlations were high between TPC and CAA values was in dgesta (R2=0.96) but not extracts (R2=0.58). Higher correlations were also obtained between CAA and chemical assays in digesta.3. The antiproliferative activities of Chinese bayberry phenolic compounds, such as gallic acid, protocatechuic acid, chlorogenic acid, p-hydroxybenzoic acid, p-coumaric acid, caffeic acid, vanillic acid, ferulic acid, cyanidin-3-o-glycosid and myricetin, were investigated. We found that protocatechuic acid, chlorogenic acid,p-hydroxybenzoic acid, p-coumaric acid, vanillic acid, ferulic acid and cyanidin-3-o-glycoside have little effect on the proliferation of ovarian cancer cells. The other phenolic compounds exhibited the inhibitory effects on ovarian cancer cells as follows:myricetin> gallic acids> cyanidin-3-o-glycosid. Galangin was also an object of study due to its similar structure with myricetin.4. In this study, we found myricetin and galangin exhibited greater cytotoxicity than cisplatin in two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and they were less cytotoxic to a normal ovarian cell line, IOSE 364. They selectively induced apoptosis in both cisplatin-resistant cancer cell lines, but didn’t induce apoptosis in the normal ovarian cell line. Myricetin induced both Bcl-2 family dependent intrinsic and DR5 dependent extrinsic apoptosis in OVCAR-3 cells. P53, a multifunctional tumor suppressor, regulated apoptosis in OVCAR-3 cells through a Bcl-2 family protein dependent pathway. Myricetin and galangin did not induce cell cycle arrest in either ovarian cancer cell line. Because of their potency and selectivity against cisplatin-resistant cancer cells, myricetin and galangin could potentially be used to overcome cancer chemoresistance against platinum-based therapy.5. In this study, anti-angiogenic effects of myricetin and galangin were investigated with in vitro (HUVEC) and in vivo (CAM) models, which showed that they inhibited angiogenesis induced by OVCAR-3 cells. The molecular mechanisms through which myricetin and galangin suppress angiogenesis were also studied. It was observed that myricetin and galangin inhibited secretion of the key angiogenesis mediator vascular endothelial growth factor (VEGF) and decreased levels of p-Akt, p-p70S6K and hypoxia-inducible factor-1α (HIF-1α) proteins in A2780/CP70 and OVCAR-3 cells. Transient transfection experiments showed that myricetin and galangin inhibited secretion of VEGF by the Akt/p70S6K/HIF-1α protein. Moreover, myricetin inhibited the HIF-1α and VEGF expression in OVCAR-3 cells through increasing p21 protein. These data suggest that myricetin and galangin might serve as potential anti-angiogenic agents in the prevention of ovarian cancers dependent on new blood vessel networks.