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

Authors

Aaron C. Spalding, University of Michigan Medical School
Benjamin David Zeitlin, University of the PacificFollow
Kari Wilder-Romans, University of Michigan Medical SchoolFollow
Mary Ellen Davis, University of Michigan Medical SchoolFollow
Jacques E. Nör, University of Michigan School of DentistryFollow
Theodore S. Lawrence, University of Michigan, School of MedicineFollow
Edgar Ben-Josef, University of PennylvaniaFollow

ORCiD

Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188

Department

Biomedical Sciences

Document Type

Article

Publication Title

Translational Oncology

ISSN

1936-5233

Volume

1

Issue

4

DOI

10.1593/tlo.08151

First Page

195

Publication Date

Winter 12-1-2008

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 (PKC beta) that phosphorylates GSK3 beta to suppress apoptosis and promote endothelial cell proliferation and microvessel formation. We used Enzastaurin (Enz) to test the hypothesis that inhibition of PKC beta results in radiosensitization of endothelial cells in culture and in vivo. MATERIALS/METHODS: We measured PKC beta 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 PKC beta 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 GSK3 beta 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 PKC beta 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 PKC beta inhibition with radiation and further investigating such regimens in pancreatic cancer.

Recommended Citation

Spalding, A. C., Zeitlin, B. D., Wilder-Romans, K., Davis, M. E., Nör, J. E., Lawrence, T. S., & Ben-Josef, E. (2008). Enzastaurin, an inhibitor of PKC beta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells.. Translational Oncology, 1(4), 195. DOI: 10.1593/tlo.08151
https://scholarlycommons.pacific.edu/dugoni-facarticles/389

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