Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin

Abstract

Bryostatin 1, like the phorbol esters, activates protein kinase C. However, bryostatin 1 induces only some of the effects in cultured cells which result from phorbol ester treatment, whereas it blocks other responses to the phorbol esters. In mouse keratinocytes in particular, bryostatin 1 induces ornithine decarboxylase, a marker of proliferation, but blocks induction of markers of differentiation. Because of the postulated role of induction of differentiation in tumor promotion, we have now examined bryostatin 1 as a tumor promoter and as an inhibitor of phorbol ester tumor promotion in the initiation—promotion model of skin carcinogenesis. After initiation with 7,12-dimethylbenz[a]anthracene, weekly topical treatments of the backs of mice with 1 μg(1.1 nmol) bryostatin 1 induced epidermal hyperplasia and inflammation, although not to the extent seen after treatment with the promoter 12- O -tetradecanoylphorbol-13-acetate (TPA). Treatment with bryostatin 15 min before each TPA exposure reduced the phorbol ester-induced hyperplasia. Bryostatin 1 was ineffective as a complete tumor promoter and displayed very weak activity as a second stage promoter upon treatment of initiated mice for 30 weeks. Combined exposure of mice to bryostatin 1 and TPA resulted in a substantial inhibition of promotion by TPA. Our in vivo results extend earlier in vitro findings that bryostatin 1 acts as a partial inhibitor of protein kinease C function.