Abstract
It has been widely recognized that induction of Phase 2 enzymes is an effective and sufficient strategy for achieving protection against carcinogenesis. Nrf2 is the unifying master regulator of these enzymes and its activation in various tissues, including the urinary bladder, is associated with inhibition of carcinogenesis. 5,6-Dihydrocyclopenta[c][1,2]-dithiole-3(4H)-thione (CPDT) is a highly potent inducer of Phase 2 enzymes and an activator of Nrf2. In vivo, it is particularly effective in the bladder, showing significant effects in this tissue when dosed to rats at levels as low as 0.98 micromol/(kgday) (0.17 mg/(kg day)). The activities of key Phase 2 enzymes, including glutathione S-transferase, NAD(P)H:quinone:oxidoreductase 1 and glutamate cysteine synthetase, and levels of glutathione were elevated by CPDT in rat bladder in vivo and in cultured bladder cells in vitro. In the bladder, enzyme induction and Nrf2 activation appear to occur exclusively in the epithelium. This is highly significant, since almost all bladder cancers develop from the epithelium. Studies in cultured bladder cells using siRNA to knock down Nrf2 or in cells with total Nrf2 knockout showed that the ability of CPDT to induce Phase 2 enzymes depends completely on Nrf2. In conclusion, CPDT potently and preferentially induces Phase 2 enzymes in the bladder epithelium and Nrf2 is its key mediator.