| Epidemiological studies have revealed an inverse correlation between the intake of cruciferous vegetables and the risk of cancer. Many experimental animal studies suggest that the anti-cancerous effect of cruciferous vegetables can be ascribed to a high abundance of glucosinolates, chemical precursors of chemopreventive isothiocyanates. Although the molecular pathways mediating the anti-tumoral effects of isothicyanates, such as phenethyl isothiocyanate (PEITC) and sulforaphane, have not been fully elucidated, it is known that they strongly induce phase II detoxifying enzymes (HO-1, NQO1 and UGT1A1) by NF-E2-related factor 2 (Nrf2)-mediated activation of antioxidant response element (ARE), which is positively regulated by ERK1/2 and JNK1/2, but negatively regulated by p38 MAPK. Treatment of PEITC or sulforaphane activated ERK1/2 and JNK1/2, but inhibited anisomycin-induced activation of p38 MAPK isoforms. In pursuit of synthetic isothiocyanates that exhibit strong ARE-dependent gene activation, 3-morpholinorpropyl isothiocyanate (3-MP-ITC) was identified as a novel isothiocyanate, whose ARE activation was superior to PEITC and sulforaphane. While continued intraperitoneal injection of curcumin or PEITC, beginning a day before tumor implantation significantly retarded the growth of PC-3 xenografts in nude mice, curcumin and PEITC in combination, but not PEITC or curcumin alone, significantly suppressed the growth of established PC-3 xenografts. Also, oral administration of broccoli sprouts for 16 weeks significantly inhibited the prostate tumor growth in TRAMP mice not only by the induction of Nrf2 and apoptosis, but also by the suppression of Akt/mTOR pathway. Finally, exposure of a phenolic antioxidant, butylated hydroxyanisole (BHA) or its metabolite, tert-butyl hydroquinone (tBHQ) to primary-cultured human and rat hepatocytes strongly activated ERK1/2 and JNK1/2 and induced Nrf2, HO-1 and NQO1 proteins. This dissertation clearly demonstrates that isothiocyanates induce Nrf2/ARE-dependent gene activation and the expression of phase II detoxifying enzymes by activating ERK1/2 and JNK1/2 and inhibiting p38 MAPK pathways. Also, it provides the clear evidence of prostate carcinogenesis suppression by isothiocyanates and the underlying biochemical mechanisms in vivo. Together, this dissertation will contribute to better understanding how chemopreventive isothiocyanates regulate the cellular protective mechanisms and prevent against prostate carcinogenesis. |
