Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation

Christopher D. Willey, Dakai Xiao, Tianxiang Tu, Kwang Woon Kim, Luigi Moretti, Kenneth J. Niermann, Mohammed N. Tawtawy, Chad C. Quarles, Bo Lu

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Purpose: Angiogenesis has generated interest in oncology because of its important role in cancer growth and progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation. Methods and Materials: The combination of the selective PKCβ inhibitor Enzastaurin (ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and human umbilical vascular endothelial cells (HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays, and Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry. Results: ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared with either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed. Conclusion: PKC appears to be crucial for angiogenesis, and its inhibition by ENZ has potential to enhance radiotherapy in vivo.

Original languageEnglish (US)
Pages (from-to)1518-1526
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume77
Issue number5
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

Keywords

  • Angiogenesis
  • Enzastaurin
  • Lung cancer
  • PKC
  • Radiation

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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    Willey, C. D., Xiao, D., Tu, T., Kim, K. W., Moretti, L., Niermann, K. J., Tawtawy, M. N., Quarles, C. C., & Lu, B. (2010). Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation. International Journal of Radiation Oncology Biology Physics, 77(5), 1518-1526. https://doi.org/10.1016/j.ijrobp.2009.06.044