Pretreatment of CD-1 mouse skin with
prostratin (12-deoxyphorbol 13-acetate) inhibited
biological response to
phorbol 12-myristate 13-acetate. The three responses examined were
hyperplasia, induction of
ornithine decarboxylase, and
edema; the characteristics of inhibition depended on the specific response.
Hyperplasia is the best short-term correlate of
tumor promotion. Two or more pretreatments with 2.56 mumol (1 mg)
prostratin, administered at intervals of 1-4 days, almost completely blocked the
hyperplasia induced by
phorbol 12-myristate 13-acetate applied 15 min to 6 h after the last pretreatment. Inducibility of
hyperplasia was partially restored at 2 days and recovered by 4 days.
Prostratin was more potent for inhibition of
ornithine decarboxylase induction (50% inhibitory dose = 25.6 nmol) than it was for
hyperplasia: the inhibition was largely attained by the first application, and the recovery from inhibition was slower (8 days).
Edema was partially inhibited by
prostratin (dose giving 50% of maximal inhibition = 512 nmol). We have previously demonstrated that
prostratin is a
protein kinase C activator. Our present results show that
prostratin is a functional antagonist for a class of
protein kinase C mediated responses. The findings emphasize the diversity of
biological outcome for
protein kinase C activators, presumably driven by the extensive heterogeneity in the
protein kinase C pathway.