Prostate cancer chemoprevention by dietary phytochemicals.

摘要

Prostate cancer is one of the most frequent diagnosed forms of cancer among men in the United States. It displays considerable clinical, morphological and biological heterogeneity. Integrated information regarding candidate genes, transcription factors and pathways implicated in prostate cancer development is crucial to help stall prostate cancer. Currently the number of patients suffering from this invasive disease is on the rise and given the fact that when clinically significant this disorder is associated with a high mortality rate, prevention may prove to be the best approach. Chemoprevention entails the use of preferably dietary agents to block or suppress the various stages of prostate carcinogenesis. Flavonoids, the essential components of fruits and vegetables can modulate transcription factor AP-1 and its upstream signaling cascades mainly ERK-MAPK and JNK-MAPK in human androgen insensitive prostate cancer (PC3) cells. Soy isoflavone concentrate can upregulate the expression of several phase II detoxifying and antioxidant genes in an NF-E2-related factor 2 (Nrf2) dependent manner. In addition to detoxifying genes, soy isoflavone concentrate can also modulate the expression of genes such as LATS2, GREB1, calpain and many more in an Nrf2 dependent manner. The expression of most of these genes has been shown to be altered in prostate cancer progression. Animal models that can mimick key events in prostate cancer progression provide a valuable tool in the development of anti cancer therapies. In one such transgenic model, curcumin or PEITC suppressed high grade PIN levels. However a combination of low doses of these agents worked remarkably well in suppressing tumors all together. A deeper insight at the process of cancer development in the same model revealed that indeed prostate carcinogenesis occurs by progressive suppression of Nrf2 and its related phase II detoxifying and antioxidant enzymes. Treatment with gamma-tocopherol enriched mixed tocopherol diet, on the other hand, significantly increased expression of Nrf2 as well as phase II detoxifying and antioxidant enzymes. Likewise a mixed tocotrienol diet suppressed tumor incidence by modulating cell cycle control and proapoptotic proteins. Finally, the observed chemopreventive effects of the dietary agents were correlated with their and their metabolites' circulating plasma levels.