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Investigated if carcinogen defense (phase 2) enzymes could be induced in the prostate …

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- Modest induction of phase 2 enzyme activity in the F-344 rat prostate

The most commonly diagnosed cancer among men, prostate cancer will account for nearly 30,000 deaths in the United States in 2005 and cause countless men to suffer significant morbidity [1]. Accumulating evidence implicates oxidative damage, possibly due to prostatic inflammation, as an important contributor to prostate carcinogenesis [2]. Some human prostate cells appear to acquire increased susceptibility to oxidative DNA damage because they lack expression of glutathione S-transferase-π (GSTP1) due to somatically acquired methylation of deoxycytidine residues in "CpG islands" in the 5'-regulatory region of the GSTP1 gene early in prostate carcinogenesis [3-6]. GSTP1 is an important member of the class of enzymes (phase 2 enzymes) that protect cells against electrophilic compounds, including many carcinogens and oxidative species [7]. Strategies to induce the expression and activity of phase 2 enzymes have been shown to protect against carcinogenesis in a variety of organ sites and across several species [8,9]. Since prostate cancer appears to be uniquely deficient in the phase 2 enzyme GSTP1, a rational prevention strategy might be to compensate for GSTP1 loss by global induction of phase 2 enzymes within the prostate.

A number of compounds effective at inducing phase 2 enzyme activity have been identified by screening for nicotinomide quinone oxidoreductase (NQO1) enzymatic induction in the Hepa 1c1c7 cell line [10-12]. Compounds effective at inducing phase 2 enzymatic activity in Hepa 1c1c7 cells in vitro have been found to be effective at inducing the phase 2 enzyme response in vivo, and several of these compounds have also been demonstrated to prevent against carcinogen induced tumors in animal models [11,13]. However, compounds that induce NQO1 activity in liver-derived Hepa 1c1c7 cells do not always produce induction in liver cells in vivo, and can vary in their effectiveness at inducing phase 2 enzymes in different tissues [14-16]. For instance, both tert-butyl-4-hydroxyanisole (BHA) and dimethyl fumarate are effective at inducing NQO1 activity in Hepa 1c1c7 cells in vitro, but in CD-1 mice, only BHA induces NQO1 activity in the liver (6-fold), in addition to the lung and kidney (2-fold), but not in the stomach and colon [17]. Dimethyl fumarate, on the other hand, induces NQO1 enzymatic activity in the forestomach, small intestine, kidneys and lungs, but produces little change in NQO1 activity in the liver [11].

To identify compounds effective at inducing phase 2 enzymes in human prostate cells, we have carried out a comprehensive screen of candidate phase 2 enzyme inducing agents in human prostate cancer cells in vitro and identified compounds from several chemical classes that were effective at producing modest increases in NQO1 enzymatic activity [18]. Notably, the pattern of NQO1 induction across compounds differed between prostate cancer cell lines and a human liver cell line, suggesting that there could be significant differences in the response of prostate cells to phase 2 enzyme inducing agents compared to other tissue types. We also have demonstrated that sulforaphane, an isothiocyanate found in cruciferous vegetables, induces NQO1, glutathione synthetic enzymes and glutathione transferases in several human prostate cancer cells [19].

Although we have identified compounds effective at inducing phase 2 enzymes in prostate cells in vitro, the possibility of inducing phase 2 enzyme response in the prostate in vivo has not been tested. We selected 4 candidate phase 2 enzyme inducing agents effective in prostate cells in vitro and tested whether they could induce phase 2 enzyme enzymatic activity in the prostates of F344 rats in vivo. After 5 days of gavage feeding with each of candidate compounds or vehicle alone, global GST activity, isozyme GST-mu and NQO1 activity were assessed in the prostate, liver, kidney and bladder tissues of male rats.

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