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Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells.

Abstract：

PURPOSE:Angiogenesis plays an important role in pancreas cancer pathobiology. Pancreatic tumor cells secrete vascular endothelial growth factor (VEGF), activating endothelial cell protein kinase C beta (PKCbeta) that phosphorylates GSK3beta to suppress apoptosis and promote endothelial cell proliferation and microvessel formation. We used Enzastaurin (Enz) to test the hypothesis that inhibition of PKCbeta results in radiosensitization of endothelial cells in culture and in vivo. MATERIALS/METHODS:We measured PKCbeta phosphorylation, VEGF pathway signaling, colony formation, and capillary sprout formation in primary human dermal microvessel endothelial cells (HDMECs) after Enz or radiation (RT) treatment. Microvessel density and tumor volume of human pancreatic cancer xenografts in nude mice were measured after treatment with Enz, RT, or both. RESULTS:Enz inhibited PKCbeta and radiosensitized HDMEC with an enhancement ratio of 1.31 +/- 0.05. Enz combined with RT reduced HDMEC capillary sprouting to a greater extent than either agent alone. Enz prevented radiation-induced GSK3beta phosphorylation of serine 9 while having no direct effect on VEGFR phosphorylation. Treatment of xenografts with Enz and radiation produced greater reductions in microvessel density than either treatment alone. The reduction in microvessel density corresponded with increased tumor growth delay. CONCLUSIONS:Enz-induced PKCbeta inhibition radiosensitizes human endothelial cells and enhances the antiangiogenic effects of RT. The combination of Enz and RT reduced microvessel density and resulted in increased growth delay in pancreatic cancer xenografts, without increase in toxicity. These results provide the rationale for combining PKCbeta inhibition with radiation and further investigating such regimens in pancreatic cancer.

journal_name

Transl Oncol

journal_title

Translational oncology

authors

Spalding AC,Zeitlin BD,Wilder-Romans K,Davis ME,Nor JE,Lawrence TS,Ben-Josef E

doi

10.1593/tlo.08151

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

195-201

issue

issn

1936-5233

journal_volume

pub_type

杂志文章

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Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells.