Chemoprevention of prostate cancer and anti-inflammatory effect by phytochemicals

• Main Authors: Feng-Lan Chiu, 邱鳳蘭
• Other Authors: 林仁混
• Format: Others
• Language: en_US
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/69972159142863602542

博士 === 臺灣大學 === 生物化學暨分子生物學研究所 === 96 === Prostate cancer is the most common cancer in American men and the second leading cause of cancer death in this population. It is well known that there are significant differences in the incidence of certain types of cancer in particular countries or regions of the world. The incidence of clinically significant prostate cancer is vastly different between Western and East Asia countries. A difference points to factors in the ‘Western life-style’ fostering prostate cancer. One candidate is a diet rich in saturated fat and relatively low in vitamins and micronutrients from fruit and vegetables. Androgen receptors play a critical role in regulating the growth, proliferation and progression in prostate carcinoma and androgen-refractory prostate cancer. Recent studies have suggested that prostate cancer cell proliferation is inhibited by AR downregulation. Hence, a therapy approach are focus on how to inhibiting AR expression and/or blocking the AR-mediated signaling. In chapter 2, our aim was to investigate luteolin, a flavonoid, affects AR expression and function in prostate cancer cells and xenografts. Luteolin inhibited LNCaP cell growth and the expression of androgen regulated PSA genes. Moreover, luteolin treatment resulted in repressing androgen-dependent trans-activation of AR by inhibiting AR nuclear translocation. Western blot analysis demonstrated that AR protein expression was inhibited by luteolin in dose- and time-dependent manners. Luteolin decreased the association of AR and heat shock protein 90 (Hsp90), which in turn induced AR degradation through proteasome-mediated pathway in ligand-independent manner. Our results also demonstrate that luteolin suppressed LNCaP xenograft tumor growth, PSA secretion, and AR protein expression in severe combined immunodeficient (SCID) mice. Recurrent or chronic inflammation has been implicated in the development of many human cancers, including those of the esophagus, stomach, liver, large intestine, urinary bladder and prostate. In clinical chemopreventive trials, using aspirin or NASIDs could suppress the incidence of many cancers, such as colon cancer, breast cancer, and prostate cancer. Hence, our study used the LPS-stimulated macrophage as an inflammation model to investigate the effect of O-methylated EGCG derivatives and steroidal alkaloids on anti-inflammation effects, and find more potent and other valuable compounds for anti-inflammation disorders. Tea polyphenols have been reported to act in ways that are antioxidative, antimutagenic effects, anticarcinogenic, and antiallergic activity. (-)-Epigallocatechin-3-gallate (EGCG), a major tea polyphenol, undergo substantial biotransformation to different derivatives that includes the methylated compounds. Recent researches have showed that the O-methylated derivatives of EGCG have more effectively compared with EGCG on biological impacts. In the part 1 of chapter 3, we compare the three O-methylation derivatives of EGCG ((-)-Epigallocatechin-3-O-(3-O-methyl)gallate (3"Me-EGCG), (-)-Epigallocatechin-3-O-(4-O-methyl)gallate (4"Me-EGCG) and (-)-4''-methyl epigallocatechin-3-O-(4-O-methyl)gallate (4'',4"-diMe-EGCG)) to EGCG on the anti-inflammatory effects. We found that 3"Me-EGCG has higher inhibitory effect on the nitric oxide generation and iNOS and COX-2 expression as compared with EGCG, while 4"Me-EGCG and 4'',4"-diMe-EGCG were less effective. In addition, we have investigated the composition of the three O-methylated EGCG derivatives, 3"Me-EGCG, 4"Me-EGCG, and 4'',4"-diMe-EGCG in tea leaves by HPLC. We found that different content of these O-methylated EGCG show in various fresh tea leaves. Neither fresh tea leaves nor commercial tea leaves could detect the 4'',4"-diMe-EGCG. Higher levels of 3"Me-EGCG and 4"Me-EGCG were detected in Chinshin-Kanzai (a species of Camellia Sinensis) cultivated in the mountain area of Sansia, Taipei County, Taiwan. Also, these O-methylated EGCG were found to be higher in autumn and winter than spring and summer. The young leaves (apical bud and the two youngest leaves) were found to be richer in these O-methylated EGCG than old leaves (from the tenth to the fifth leaf). In fermentation level, the amount of O-methylated EGCG is higher in unfermented longjin green tea than semifermentated oolong tea. However, the fermentated black tea and puerh tea did not find these O-methylated EGCG. In the part 2 of chapter 3, our researches have used steroidal alkaloid as agents in order to find new compounds for anti-inflammation disorders. The structures of steroidal alkaloids, tomatidine and soalsodine, were similar as anabolic steroids, steroidal hormones, and corticosteroids. Inducible nitric oxide synthase and cyclooxygenase-2 are important enzymes that mediate inflammatory processes and associated with inflammatory diseases and cancer. However, the molecular mechanisms of anti-inflammatory effects of these steroidal alkaloids were not clear. Our results were indicated that tomatidine has more potent anti-inflammatory action as compared to solasodine and diosgenin. Tomatidine could decrease LPS-stimulated production of nitrite oxide (NO) and prostaglandin (PG) via inhibition of iNOS and COX-2 expression. Tomatidine inhibited the LPS-induced iNOS and COX-2 expression through suppression of I-kappaB α phosphorylation and NF-kappaB nuclear translocation, and JNK pathway in turns inhibited the c-jun phosphorylation and Oct-2 expression. Recent studies demonstrate that phytochemicals can protect humans against diseases and how phytochemicals interfere with this mechanism is still unclear. In this dissertation, our results demonstrated that luteolin, a naturally flavnoid, could inhibited the cell growth in prostate cancer cells and xenografts. The LPS-stimulated macrophage could be use as an inflammation model to investigate the effect of O-methylated EGCG derivatives and steroidal alkaloids on anti-inflammation effects. Our experiments found that 3"Me-EGCG and tomatidine could act as anti-inflammatory agents and may be possible to develop as useful agents for chemoprevention of cancer or inflammatory disorders. However, our preclinical research might promising and ready for further study in clinical chemopreventive trials.