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Protein kinase C-β inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis

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Summary

Radiation therapy is a widely used treatment for metastatic bone cancer, but the rapid onset of tumor radioresistance is a major problem. We investigated the radiosensitizing effect of enzastaurin, a protein kinase Cβ (PKCβ) inhibitor, on bone tumor growth and tumor-related pain. We found that enzastaurin enhanced the effect of ionizing radiation on cultured murine 4T1 breast cancer and murine endothelial cells, suppressing their proliferation and colony formation. Enzastaurin and ionizing radiation also induced caspase-mediated apoptosis of 4T1 cells to a greater degree than radiation alone. Enzastaurin treatment of 4T1 cells blocked the phosphorylation of PKCβ, as well as Ras and two of its downstream effectors ERK1/2 and RAL-GTP. Using an orthotopic model of bone metastasis, we observed that a combination of enzastaurin and localized radiation treatment reduced tumor blood vessel density, bone destruction and pain compared to single modality treatment. In conclusion, we demonstrate that inhibition of PKCβ in combination with localized radiation treatment suppresses tumor growth and alleviates pain as compared to radiation-only treatment. We also show that the radiosensitizing effect of enzastaurin is associated with suppression of tumor cell proliferation and tumor-induced angiogenesis possibly through inhibition of the Ras pathway.

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Acknowledgment

This study was partially supported by Experimental Therapeutics Fund from University of Minnesota (we are grateful to Audrey and Denis Anderson for ongoing support for this Fund) and partially by grant from Eli Lilly and Company. We thank Michael Franklin for editorial support.

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Authors and Affiliations

  1. Division of Hematology, Oncology and Transplantation Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN, 55455, USA

    Arkadiusz Z. Dudek, Pawel Zwolak, Piotr Jasinski, Kaoru Terai & Faris Farassati

  2. Department of Dermatology, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN, 55455, USA

    Nathan J. Gallus & Marna E. Ericson

Authors
  1. Arkadiusz Z. Dudek
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  2. Pawel Zwolak
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  3. Piotr Jasinski
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  4. Kaoru Terai
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Correspondence to Arkadiusz Z. Dudek.

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Dudek, A.Z., Zwolak, P., Jasinski, P. et al. Protein kinase C-β inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis. Invest New Drugs 26, 13–24 (2008). https://doi.org/10.1007/s10637-007-9079-y

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  • DOI: https://doi.org/10.1007/s10637-007-9079-y

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