In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo

Although clonogenic or divisional death is the main mechanism by which DNA- damaging agents demonstrate antitumor activity, recent data indicate that s trategies specifically designed to trigger apoptosis may also prove to be u seful antitumor agents. Protein kinase C (PKC) isoenzymes are involved in t he regulation of cell proliferation, differentiation, and survival. Whereas pharmacological inhibition of PKC activity triggers apoptosis in most mamm alian cells, cell line and tissue differences in sensitivities to these inh ibitors remain. Whereas PKC inhibitors have potential as antitumor agents, issues of kinase specificity and solubility have remained obstacles to thei r clinical use. In this report, we investigated the antitumor activity of t he PKC inhibitor chelerythrine chloride (chelerythrine), a selective inhibi tor of group A and B PKC isoforms, Chelerythrine exhibited cytotoxic activi ty against nine human tumor cell lines tested in vitro. On the basis of the finding that radioresistant and chemoresistant squamous cell carcinoma lin es (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, Sig nificantly, treatment with chelerythrine resulted in minimal toxicity. Thes e findings demonstrate a potential for chelerythrine as an antitumor drug a gainst squamous cell carcinoma.