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The Protein Kinase Cß–Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts

Lilly Research Labs, Eli Lilly and Company, Indianapolis, Indiana

Requests for reprints: Jeremy R. Graff, Principal Research Scientist, Cancer Growth and Translational Genetics, Oncology Division, Lilly Research Labs, Lilly Corporate Center, DC0546, Indianapolis, IN 46285. Phone: 317-277-0220; Fax: 317-277-3652; E-mail: graff_jeremy{at}lilly.com.

Activation of protein kinase Cß (PKCß) has been repeatedly implicated in tumor-induced angiogenesis. The PKCß-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCß has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness. Herein, we show that Enzastaurin has a direct effect on human tumor cells, inducing apoptosis and suppressing the proliferation of cultured tumor cells. Enzastaurin treatment also suppresses the phosphorylation of GSK3ß^ser9, ribosomal protein S6^S240/244, and AKT^Thr308. Oral dosing with Enzastaurin to yield plasma concentrations similar to those achieved in clinical trials significantly suppresses the growth of human glioblastoma and colon carcinoma xenografts. As in cultured tumor cells, Enzastaurin treatment suppresses the phosphorylation of GSK3ß in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3ß phosphorylation to a similar extent in peripheral blood mononuclear cells (PBMCs) from these treated mice. These data show that Enzastaurin has a direct antitumor effect and that Enzastaurin treatment suppresses GSK3ß phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3ß phosphorylation may serve as a reliable pharmacodynamic marker for Enzastaurin activity. With previously published reports, these data support the notion that Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis.

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