Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C

Piotr Jasinski, Kaoru Terai, Pawel Zwolak, Arkadiusz Z Dudek

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Enzastaurin (LY317615.HCI), a protein kinase C (PKC)-β inhibitor, has a radiosensitising effect on 4T1 murine breast cancer and human glioma cells; however, the exact mechanism of this action has not been evaluated. The present study investigated the effects of enzastaurin and gamma irradiation on PKC activity in MCF-7 human breast cancer cells in vitro and in vivo. Enzastaurin (5 μM) in combination with irradiation (2-8 Gy) produced a synergistic decline in MCF-7 clonogenic cell survival. Analysis of MCF-7 cells stained with Annexin V and 7-aminoactinomycin D showed a dose-dependent increase in apoptosis in response to enzastaurin (3, 5 and 7 μM) and irradiation (10 Gy) compared to irradiation alone. This pro-apoptotic effect was confirmed by increases in caspase-3 and -9 activity. In a MCF-7 xenograft model, irradiation with 25 Gy increased PKC-α activity by 2.5-fold compared to untreated controls, whereas PKC-ε and -βII activity was increased by 1.8-fold. Radiation-induced activation of all three anti-apoptotic isoforms of PKC was reversed by pre-treatment with enzastaurin (75 mg/kg, twice daily for 3 days). We conclude that enzastaurin has a radiosensitising effect on MCF-7 human xenograft tumours through the reversal of anti-apoptotic activation of PKC isoforms.

Original languageEnglish (US)
Pages (from-to)1315-1322
Number of pages8
JournalEuropean Journal of Cancer
Volume44
Issue number9
DOIs
StatePublished - Jun 2008

Bibliographical note

Funding Information:
This study was partially supported by the Experimental Therapeutics Fund of the University of Minnesota (We are grateful to Audrey and Dennis Anderson for their ongoing support for this Fund). We would like to thank Michael Franklin for editorial support.

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

Keywords

  • Apoptosis
  • Breast cancer
  • Clonogenic survival
  • Enzastaurin
  • Protein kinase C
  • Radiotherapy
  • α, β, ε Isoforms

Fingerprint

Dive into the research topics of 'Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C'. Together they form a unique fingerprint.

Cite this