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Molecular Cancer Therapeutics
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Preclinical Development

Targeting Radiation-Induced G2 Checkpoint Activation with the Wee-1 Inhibitor MK-1775 in Glioblastoma Cell Lines

Bhaswati Sarcar, Soumen Kahali, Antony H. Prabhu, Stuart D. Shumway, Yang Xu, Tim Demuth and Prakash Chinnaiyan
Bhaswati Sarcar
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Soumen Kahali
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Antony H. Prabhu
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Stuart D. Shumway
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Yang Xu
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Tim Demuth
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Prakash Chinnaiyan
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DOI: 10.1158/1535-7163.MCT-11-0469 Published December 2011
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Abstract

The purpose of this study was to determine the capacity of MK-1775, a potent Wee-1 inhibitor, to abrogate the radiation-induced G2 checkpoint arrest and modulate radiosensitivity in glioblastoma cell models and normal human astrocytes. The radiation-induced checkpoint response of established glioblastoma cell lines, glioblastoma neural stem (GNS) cells, and astrocytes were determined in vitro by flow cytometry and in vivo by mitosis-specific staining using immunohistochemistry. Mechanisms underlying MK-1775 radiosensitization were determined by mitotic catastrophe and γH2AX expression. Radiosensitivity was determined in vitro by the clonogenic assay and in vivo by tumor growth delay. MK-1775 abrogated the radiation-induced G2 checkpoint and enhanced radiosensitivity in established glioblastoma cell lines in vitro and in vivo, without modulating radiation response in normal human astrocytes. MK-1775 appeared to attenuate the early-phase of the G2 checkpoint arrest in GNS cell lines, although the arrest was not sustained and did not lead to increased radiosensitivity. These results show that MK-1775 can selectively enhance radiosensitivity in established glioblastoma cell lines. Further work is required to determine the role Wee-1 plays in checkpoint activation of GNS cells. Mol Cancer Ther; 10(12); 2405–14. ©2011 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received June 27, 2011.
  • Revision received September 21, 2011.
  • Accepted September 24, 2011.
  • ©2011 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 10 (12)
December 2011
Volume 10, Issue 12
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Targeting Radiation-Induced G2 Checkpoint Activation with the Wee-1 Inhibitor MK-1775 in Glioblastoma Cell Lines
Bhaswati Sarcar, Soumen Kahali, Antony H. Prabhu, Stuart D. Shumway, Yang Xu, Tim Demuth and Prakash Chinnaiyan
Mol Cancer Ther December 1 2011 (10) (12) 2405-2414; DOI: 10.1158/1535-7163.MCT-11-0469

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Targeting Radiation-Induced G2 Checkpoint Activation with the Wee-1 Inhibitor MK-1775 in Glioblastoma Cell Lines
Bhaswati Sarcar, Soumen Kahali, Antony H. Prabhu, Stuart D. Shumway, Yang Xu, Tim Demuth and Prakash Chinnaiyan
Mol Cancer Ther December 1 2011 (10) (12) 2405-2414; DOI: 10.1158/1535-7163.MCT-11-0469
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Molecular Cancer Therapeutics
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