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Lookup NU author(s): Dr Santu SahaORCiD, Dr Stuart Rundle, Dr Ioannis Kotsopoulos, Dr Jake Begbie, Rachel Howarth, Dr Isabel Pappworth, Dr Asima Mukhopadhyay, Ali Kucukmetin, Professor Kevin MarchbankORCiD, Professor Nicola CurtinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 by the authors. Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46–72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.
Author(s): Saha S, Rundle S, Kotsopoulos IC, Begbie J, Howarth R, Pappworth IY, Mukhopadhyay A, Kucukmetin A, Marchbank KJ, Curtin N
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2022
Volume: 14
Issue: 17
Print publication date: 01/09/2016
Online publication date: 01/09/2022
Acceptance date: 30/08/2022
Date deposited: 03/10/2022
ISSN (electronic): 2072-6694
Publisher: MDPI
URL: https://doi.org/10.3390/cancers14174288
DOI: 10.3390/cancers14174288
Notes: Part of the Special Issue 'Therapies in Cervical Cancer'.
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