Prostratin and 12-deoxyphorbol 13-phenylacetate (dPP) form a new class of
protein kinase C activators of unique
biological activity. Although they bind to and activate
protein kinase C, in mouse skin they either fail to induce typical
phorbol ester (PMA) effects (e.g.,
hyperplasia) or induce only partial response (e.g.,
inflammation). Furthermore, pretreatment with these agents inhibits a range of PMA induced effects (acute and chronic
hyperplasia,
inflammation, etc.) These observations suggested that
prostratin and dPP would function as inhibitors of
phorbol ester tumor promotion. Here we verify that prediction. We report that both compounds reduced both the average number of
papillomas and the
tumor incidence in a
tumor promotion schedule in CD-1 mouse skin, in which each PMA application was preceded by 12-deoxyphorbol 13-monoester pretreatment. The highest dose of
prostratin used (2.56 mumol or 1 mg/pretreatment) caused a 96% (23-fold) reduction in the average number of
papillomas with a decrease of
tumor incidence from 97 to 40%. The highest dose of dPP used (21.4 nmol or 10 micrograms/pretreatment) induced an 86% (7-fold) reduction in the average number of
papillomas with a 53% reduction of
tumor incidence from 100 to 47%. The inhibitory effect was dose dependent. The dose causing 50% inhibition was 11 nmol/pretreatment for
prostratin and 0.8 nmol/pretreatment for dPP. Maximal inhibition of
tumor promotion was accompanied by a block of epidermal
hyperplasia; however, significant inhibition of
tumor induction was observed at doses without any apparent effect on the PMA induced
hyperplasia.