Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin.
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 microgram (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 kinase C function.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D054713:Bryostatins; D004789:Enzyme Activation; D005260:Female; D006965:Hyperplasia; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D051379:Mice; D011493:Protein Kinase C / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000517:prevention & control; D013755:Tetradecanoylphorbol Acetate
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate