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DOI: 10.1055/s-0038-1640147
Dual inhibition of PARP1 and the intra-S/G2 cell cycle checkpoints as a novel strategy for highly effective radiosensitization of HPV+ HNSCC
Introduction:
The enhanced radiation sensitivity of HPV+ HNSCC is also observed on the cellular level when comparing HPV+ and HPV- HNSCC cell lines. We could show that the underlying mechanism is a defect in DNA double-strand break repair associated with a profound and sustained G2-arrest. This defect was exploited by additionally targeting the DNA damage response of these cells resulting in a further enhancement of their radiation sensitivity. We now tested a novel approach of combined targeting of PARP1 and the intra-S/G2 cell cycle checkpoints to achieve highly efficient radiosensitization.
Methods:
Western blot, immunofluorescence microscopy, colony formation assay, assessment of cell cycle distribution and flow cytometric assessment of γH2AX. PARP1 was inhibited using olaparib; intra-S/G2 checkpoint inhibition was performed using the Wee1-inhibitor AZD1775.
Results:
Enhancing CDK1/2 activity through AZD1775 resulted in reduced proliferation rates and severe replication stress. The latter was apparent from an accumulation of cells in the S-phase as well a strong increase in the replication stress & DNA damage marker γH2AX in S-phase cells. Addition of olaparib had little effect on these endpoints but resulted in a clearly enhanced radiosensitization as compared to single inhibitor usage.
Conclusion:
Combined inhibition of PARP1 and the intra-S/G2 checkpoint is a highly effective approach for radiosensitization of HPV+ HNSCC cells. It may therefore represent a viable alternative for the current standard of concomitant cisplatin-based chemotherapy and may allow for a reduction in radiation dose. The exact mechanisms of radiosensitization through this combined approach are currently being further investigated.
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No conflict of interest has been declared by the author(s).
Publication History
Publication Date:
18 April 2018 (online)
© 2018. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Georg Thieme Verlag KG
Stuttgart · New York