Besides scavenging
free radicals,
antioxidants inhibit signaling
enzymes such as
protein kinase C (PKC) that play a crucial role in
tumor promotion. By having different oxidation susceptible regions, PKC can respond to both
oxidant tumor promoters and
cancer-preventive
antioxidants to elicit opposite cellular responses.
Oxidant tumor promoters activate PKC by reacting with
zinc-thiolates present within the regulatory domain. In contrast, the oxidized forms of some
cancer-preventive agents, such as polyphenolics (
ellagic acid, 4-
hydroxytamoxifen and
curcumin) and selenocompounds, can inactivate PKC by oxidizing the vicinal
thiols present within the catalytic domain. This brings an efficient counteractive mechanism to block the signal transduction induced by
tumor promoters at the first step itself. Because
prostate cancer prevention clinical trials in large human population are under way, we have focused more on understanding the
cancer-preventive mechanism of
selenium.
Methylselenol, the postulated
cancer-preventive metabolite, has no direct effect on PKC activity. However,
methylseleninic acid, locally generated by the reaction of membrane
methylselenol with PKC-bound
tumor-promoting
fatty acid hydroperoxides, selectively inactivates PKC. This mechanism clarifies how the volatile
methylselenol that is present in a low concentration induces the inactivation of PKC selectively in the promoting precancer cells.
Selenoprotein thioredoxin reductase reverses
selenium-induced inactivation of PKC, suggesting that
selenoproteins may serve as a safeguard against the toxicity induced by selenometabolites. Moreover, this also explains how a resistance to
selenium develops in advanced malignant cells. The redox-mediated inactivation of PKC may, at least in part, be responsible for the
antioxidant-induced inhibition of
tumor promotion and cell growth, as well as for the induction of cell death.