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Radiother Oncol. 2013 Sep;108(3):495-9. doi: 10.1016/j.radonc.2013.06.035. Epub 2013 Aug 7.

HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1.

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  • 1Department of Otolaryngology and Head and Neck Surgery, University Medical Center Hamburg Eppendorf, Germany.

Abstract

PURPOSE:

Despite the comparably high cure rates observed for HPV-positive HNSCC, there is still a great need for specific tumor radiosensitization due to the often severe side effects resulting from intense radiochemotherapy. We recently demonstrated that HPV-positive HNSCC cell lines are characterized by a defect in DNA double-strand break repair associated with a pronounced G2-arrest. Here we tested whether abrogation of this radiation-induced G2-arrest by the inhibition of Chk1 results in specific radiosensitization of HPV-positive HNSCC cells.

MATERIALS AND METHODS:

Experiments were performed with five HPV and p16-positive (93-VU-147T, UM-SCC-47, UT-SCC-45, UD-SCC-2, UPCI-SCC-154) and two HPV and p16-negative HNSCC cell lines, as well as two normal human fibroblast strains. Chk1 was inhibited by the selective inhibitor PF-00477736. Cell cycle distribution was determined by flow cytometry, Chk1-activity via Western blot and cell survival by colony formation assay.

RESULTS:

With the exception of UPCI-SCC-154, the inhibition of Chk1 was found to abolish the pronounced radiation-induced G2-arrest in all HPV-positive cells utilized. All tumor cell lines that demonstrated the abrogation of G2-arrest also demonstrated radiosensitization. Notably, in G1-arrest-proficient normal human fibroblasts no radiosensitization was induced.

CONCLUSION:

Abrogation of the G2 checkpoint through the inhibition of Chk1 may be used to selectively increase the cellular radiosensitivity of HPV-positive HNSCC without affecting the surrounding normal tissue.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

Chk1; G2-arrest; HNSCC; HPV; Radiosensitivity; p16

PMID:
23932155
[PubMed - indexed for MEDLINE]
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