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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.
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