The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts
| Autor: | Philip W. Iversen, Donald Thornton, Ann M. McNulty, Sandaruwan Geeganage, Karen L. Huss, Thomas J. Brown, Luna Musib, Robert M. Campbell, Andrew Capen, Blake Lee Neubauer, Crystal Banks, Lillian Sams, Spring N. Bailey, Rebecca L. Lynch, Robin L. Goode, Jason E. Lewis, Bruce W. Konicek, Kimberly R. Hanna, Jeremy R. Graff |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Cancer Research Indoles Angiogenesis Mice Nude Apoptosis Cell Growth Processes Biology Protein Serine-Threonine Kinases chemistry.chemical_compound Glycogen Synthase Kinase 3 Mice Enzastaurin Proto-Oncogene Proteins Protein Kinase C beta Animals Humans Phosphorylation Protein kinase A Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Protein Kinase C Ribosomal Protein S6 Glycogen Synthase Kinase 3 beta Prostatic Neoplasms HCT116 Cells Xenograft Model Antitumor Assays Oncology chemistry Ribosomal protein s6 Colonic Neoplasms Cancer research Female Signal transduction Glioblastoma Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer research. 65(16) |
| ISSN: | 0008-5472 |
| Popis: | Activation of protein kinase Cβ (PKCβ) has been repeatedly implicated in tumor-induced angiogenesis. The PKCβ-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCβ 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 GSK3βser9, ribosomal protein S6S240/244, and AKTThr308. 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 GSK3β in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3β 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 GSK3β phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3β 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. |
| Databáze: | OpenAIRE |
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