ucn-1028-c and Carcinoma--Lewis-Lung

The involvement of protein kinase c (PKC) in the mechanism underlying the antimetastatic properties of triazenes was studied in C57BL/6 mice bearing Lewis lung carcinoma (3LL). In vivo and in vitro treatment with temozolomide, an in-vitro active analogue of dacarbazine, or calphostin c produced a concentration-dependent reduction of spontaneous and artificial metastases. Both agents reduced the ability of 3LL cells to adhere to endothelium. Diethylaminoethyl (DEAE)-sepharose chromatography of cell extracts revealed that incubation of 3LL cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) caused a rapid translocation of protein kinase c activity from cytosol to the membrane fraction. Membrane PKC activity induced by TPA was reduced by 60% after treatment with temozolomide. Coincident with these changes, TPA induced phosphorylation of alpha-6 integrin, whereas temozolomide or calphostin c abolished the appearance of this phosphoprotein. These results suggest that temozolomide reduced metastatic potential by interfering with alpha-6 phosphorylation induced by PKC activation.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Adhesion; Cell Membrane; Dacarbazine; Dose-Response Relationship, Drug; Integrin alpha6; Integrins; Male; Mice; Mice, Inbred C57BL; Naphthalenes; Phosphorylation; Protein Kinase C; Temozolomide; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured