Prostate cancer is the most commonly diagnosed cancer except skin cancer in the United Stares. Gossypol, a natural polyphenolic compound present in cottonseeds, possesses anti-proliferative and pro-apoptotic effects in various cancer cells. The (-)-gossypol enantiomer is a more potent inhibitor of cancer cell growth than (+)- or (±)-gossypol. In this dissertation, we hypothesize that (-)-gossypol serves as a chemopreventive agent through suppressing cell growth, inducing apoptosis and reducing metastasis in prostate cancer cells.
Firstly, we demonstrated that (-)-gossypol reduced cell viability in human primary cultured prostate cancer epithelial cells, as well as human and rat prostate cancer cell lines. The growth inhibition caused by (-)-gossypol treatment was associate with down-regulation of cyclin-D1 and Rb, but with up-regulation of p21 and TGF-β1 expression at mRNA and/or protein levels. Secondly, prostate cancer cells treated with (-)-gossypol induced apoptosis measured by DNA fragmentation. (-)-Gossypol treatment inhibited the anti-apoptotic Bcl-2 and Bcl-xL protein expression, but increased the pro-apoptotic Bax, and Bak protein expression. Consequently, the activations of caspase-3, -8 and -9 were observed, and the further activations of apoptotic downstream proteins, such as PARP and DFF 40, were found. The apoptotic effect was abolished by caspase inhibitors indicated a caspase-dependent pathway of (-)-gossypol-induced cell death. Thirdly, (-)-gossypol-induced apoptosis was associated the Bcl-xL inhibition through transcription repression and was independent of the level of Bcl-xL protein in cancer cells. Our data showed that (-)-gossypol treatment elevated the p53 protein, which subsequently up-regulated the expression of its downstream proteins p21 and PUMA, and p53 played a role, at least in part, in (-)-gossypol-induced apoptosis. Finally, (-)-gossypol was able to reduce cell invasiveness in MAT-LyLu cells, and MLL cells, a subline of the MAT-LyLu cells from the metastasized lungs of MAT-LyLu-bearing Copenhagen rats. (-)-Gossypol treatment induced the dose-dependence of growth inhibition, colony formation and in vitro invasive activity in both MLL and MAT-LyLu cells.
Our data suggest that (-)-gossypol might serve as a chemotherapeutic and chemopreventive agent for prostate cancer. To develop (-)-gossypol-enriched foods such as cottonseed oil or cottonseed meal flour might have chemopreventive effect for healthy human individuals as well as prostate cancer patients.