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Specific Binding to Protein Kinase C by Ingenol and Its Induction of Biological Responses

Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892

We have examined the ability of ingenol to bind to and activate protein kinase C and to induce similar responses to the phorbol esters in biological systems. The rationale was that ingenol possesses the critical functionalities of the phorbol ester pharmacophore with the exception of the hydrophobic domain; it might therefore possess weak potency, although previous reports had indicated that ingenol was biologically inactive. Our data demonstrate that ingenol indeed binds to protein kinase C with a K_i of 30 µM and activates the enzyme. In addition, ingenol was biologically active in 3 separate cell systems, showing effects similar to the phorbol esters on morphological change, cell-cell communication, epidermal growth factor binding, arachidonic acid metabolite release, and ornithine decarboxylase activity. The 50% effective concentration values for the biological activity of ingenol were between 30 µM and 1 mM, varying somewhat with the cell system and type of response. The biological activity of ingenol in general supports the proposed models of the phorbol ester pharmacophore and imposes additional experimental constraints that the modeling must satisfy.

¹ To whom requests for reprints should be addressed, at: Laboratory of Cellular Carcinogenesis and Tumor Promotion, Building 37-3B25, National Cancer Institute, Bethesda, MD 20892.

Received 6/ 3/91. Accepted 10/16/91.