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Investigational New Drugs
Published in: Investigational New Drugs 1/2008

01-02-2008 | Preclinical Studies

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

Authors: Arkadiusz Z. Dudek, Pawel Zwolak, Piotr Jasinski, Kaoru Terai, Nathan J. Gallus, Marna E. Ericson, Faris Farassati

Published in: Investigational New Drugs | Issue 1/2008

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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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Metadata
Title
Protein kinase C-β inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis
Authors
Arkadiusz Z. Dudek
Pawel Zwolak
Piotr Jasinski
Kaoru Terai
Nathan J. Gallus
Marna E. Ericson
Faris Farassati
Publication date
01-02-2008
Publisher
Springer US
Published in
Investigational New Drugs / Issue 1/2008
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-007-9079-y

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