Comparison of The Effects of Tangeretin and 5-demethyltangeretin on Anti-inflammation and Cancer Chemoprevention

• Main Authors: Chung, Chieh-Han, 鍾杰翰
• Other Authors: Pan, Min-Hsiung
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/xjk6hy

碩士 === 國立高雄海洋科技大學 === 水產食品科學研究所 === 100 === part 1 Tangeretin (TAN) is well documented to possess various bio-functionalities. However, recent emerging researches discovered that hydroxylation of TAN at C5 position transform TAN into its hydroxylated counterpart, 5-demethyltangeretin (5-DTAN), which may exhibit higher bio-efficacy. In this study, the anti-carcinogenesis activities of TAN and 5-DTAN were comparably evaluated by 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-O-Tetradecanoylphorbol-13-acetate (TPA) induced two-stage mouse skin carcinogenesis model. From result of this study, TAN (5μmol) treatment decreases tumor incidence by ~25%, while 5-DTAN (5μmol) decresases tumor incidence even more significantly by ~36%. Mechanistic studies reveal that TAN and 5-DTAN reduced the expression of inflammatory enzymes, cyclooxygenase-2 (COX-2), in skin tumor. TAN and 5-DTAN significantly attenuated the DNA binding of nuclear factor-B (NF-B), one of the transcription factors that regulate COX-2 expression, in DMBA/TPA-stimulated mouse skin tumor. As NF-B is a downstream target of phosphatidylinositol 3-kinase (PI3K) and AKT, we find that 5-DTAN treatment to mouse skin exhibited higher suppression of DMBA/TPA-induced activation of PI3K and phosphorylation of Akt than TAN. The inhibitory effects of 5-DTAN on DMBA/TPA-induced NF-B activation, COX-2 expression through modulation of PI3K/Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. In addition, 5-DTAN treatment not only inhibits cellular proliferation, but induces apoptosis in two-stage mouse skin carcinogenesis. 5-DTAN application induces the expression of pro-apoptotic protein Bax with concomitant decrease in anti-apoptotic protein Bcl-2. Alteration in Bax/Bcl2 ratio by 5-DTAN treatment resulted in apoptosis, which is associated with the release of cytochrome c as well as presence cleaved fragments of caspase-3. These findings demonstrate that 5-DTAN induces apoptosis through regulation of Bax/Bcl-2 ratio in mouse skin tumors. Taken together, our results clearly illustrated that 5-DTAN impart better suppressive activity than TAN and accentuate that development of therapies/chemoprevention using agents will be more beneficial against skin cancer. part 2 Tangeretin (TAN), a polymethoxyflavone, is found in the peel of citrus fruits. TAN have been reported to exhibit a wide spectrum of biological activity. However, recent emerging researches discovered that hydroxylation of TAN at C5 position transform TAN into its hydroxylated counterpart, 5-hydroxy-6,7,8,4’- tetramethoxyflavone (5-DTAN), which may exhibit higher bio-efficacy. In present study aims to evaluate the combinatorial chemopreventive effects of TAN and 5-DTAN in suppressing aberrant crypt foci (ACF) and colon carcinogenesis by azoxymethane (AOM). From result of this study, TAN (20 mg/kg) and 5-DTAN (20 mg/kg) decreased the number of ACF in colonic tissues of mice, while combination of both at low does (TAN 10 mg/kg and 5-DTAN 10 mg/kg) synergistically decrease number of ACF even more significantly. This combination also significantly regressed number of lymphoid nodules. Molecular studies revealed that exhibited the anti-proliferative, anti-inflammatory activity of TAN and 5-DTAN by decrease the levels of COX-2, cyclin D1 and c-myc through interfering with PI3K/Akt and Wnt/-catenin signaling pathways as well as the activation of transcription factors NF-B, however, combination of TAN and 5-DTAN even more decreased expression of proliferation and inflammation in colonic tissue, thus resulted in suppression of colonic tumorigenesis. Taken together, these results for the first time clearly demonstrate that TAN and 5-DTAN in combination impart better suppressive activity than either of these agents alone and accentuate that development of novel combination chemoprevention using dietary agents will be more beneficial against.