Inhibition of chrysarobin skin tumor promotion in SENCAR mice by antioxidants.

The present study was designed to further investigate the role of reactive oxygen species in the mechanism of action of anthrone tumor promoters. To accomplish this, the effects of several antioxidants on the induction of epidermal ornithine decarboxylase (ODC) activity, epidermal hyperplasia, skin edema, and skin tumor promotion by chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) were tested. Ascorbyl palmitate (AP), given 5 min prior to the promoter at 1 and 4 mumol doses, effectively inhibited the induction of ODC activity (28% and 59%, respectively) by 220 nmol of chrysarobin. Using a similar protocol, alpha-tocopherol acetate (alpha-TA) at 10 and 40 mumol doses also effectively inhibited the induction of ODC activity (36% and 70%, respectively) by 220 nmol of chrysarobin. In contrast, butylated hydroxyanisole (BHA) at doses up to 56 mumol per mouse was ineffective at inhibiting the induction of ODC by chrysarobin. AP at the 4 mumol dose significantly inhibited the induction of edema by chrysarobin by 24% and the induction of epidermal hyperplasia by 23%. alpha-TA at the 40 mumol dose also significantly inhibited chrysarobin-induced edema by 22% and epidermal hyperplasia by 17%. Skin tumor promotion in mice initiated with 25 nmol of 7,12-dimethylbenz[a]anthracene and promoted with once-weekly treatments of 220 nmol chrysarobin was markedly inhibited by treating mice with either AP or alpha-TA 5 min prior to promoter treatment. AP at 1 and 4 mumol doses significantly reduced the number of papillomas per mouse, by 48% and 44%, respectively. alpha-TA at 10 and 40 mumol doses also significantly reduced the number of papillomas per mouse, by 33% and 59%, respectively. In two separate tumor experiments, BHA at 2.8 and 5.6 mumol failed to inhibit chrysarobin tumor promotion. The current results provide further support for a role of reactive oxygen species in the tumor promoting activity of anthrones. In addition, the data indicate that the phenolic antioxidant BHA is an ineffective inhibitor of anthrone tumor promotion.