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In Vitro and in Vivo Activity of Protein Kinase C Inhibitor Chelerythrine Chloride Induces Tumor Cell Toxicity and Growth Delay in Vivo¹

Departments of Pathology [S. J. C., A. C.], Radiation and Cellular Oncology [H. J. M., R. R. W.], and Medicine [M. E. D.], Division of Biological Sciences, University of Chicago and the Pritzker School of Medicine, Chicago, Illinois 60637, and Cancer Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [D. W. K.]

Although clonogenic or divisional death is the main mechanism by which DNA-damaging agents demonstrate antitumor activity, recent data indicate that strategies specifically designed to trigger apoptosis may also prove to be useful antitumor agents. Protein kinase C (PKC) isoenzymes are involved in the regulation of cell proliferation, differentiation, and survival. Whereas pharmacological inhibition of PKC activity triggers apoptosis in most mammalian cells, cell line and tissue differences in sensitivities to these inhibitors remain. Whereas PKC inhibitors have potential as antitumor agents, issues of kinase specificity and solubility have remained obstacles to their clinical use. In this report, we investigated the antitumor activity of the PKC inhibitor chelerythrine chloride (chelerythrine), a selective inhibitor of group A and B PKC isoforms. Chelerythrine exhibited cytotoxic activity against nine human tumor cell lines tested in vitro. On the basis of the finding that radioresistant and chemoresistant squamous cell carcinoma lines (HNSCC) undergo apoptosis rapidly after treatment with chelerythrine in vitro, we assessed the effects of this agent on p53-deficient SQ-20B HNSCC cells in vivo. The results demonstrate that chelerythrine treatment of nude mice bearing SQ-20B is associated with significant tumor growth delay. Significantly, treatment with chelerythrine resulted in minimal toxicity. These findings demonstrate a potential for chelerythrine as an antitumor drug against squamous cell carcinoma.

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