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Abstract

Differences in Durability of PARP Inhibition by PARP Inhibitors in Ovarian Cancer Cells †

1
Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle upon Tyne NE1 7RU, UK
2
Chittaranjan National Cancer Institute, 37 SP Mukherjee Road, Kolkata 700026, India
3
Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK
*
Author to whom correspondence should be addressed.
Presented at the 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response, 1–14 February 2021; Available online: https://iecc2021.sciforum.net/.
Academic Editor: Helen E. Bryant
Med. Sci. Forum 2021, 3(1), 11; https://doi.org/10.3390/IECC2021-09194
Published: 29 January 2021
Background: PARP inhibitors (PARPi) exploit defects in homologous recombination repair (HRR) to selectively kill tumour cells. Continuous PARP inhibition is required for cytotoxicity. PARPis rucaparib, olaparib, and niraparib have been approved for use in ovarian cancer on continuous schedules. Previous studies demonstrate prolonged PARP inhibition by rucaparib [1]. Aim: To determine if persistent PARP inhibition is a class effect. Methods: IGROV-1 (human ovarian cancer) cells were treated with 1 µM of rucaparib, olaparib, niraparib, talazoparib, or pamiparib for 1 h before drug was washed off and replaced with fresh media for 0, 1, 24, 48, or 72 h prior to harvesting. Cellular PARP activity was measured using a GCLP-validated assay [2] in comparison with untreated controls and where 1 µM inhibitor was added to the reaction. Results: rucaparib, olaparib, niraparib, talazoparib, and pamiparib each inhibited PARP activity in permeabilized cells > 99% when 1 µM was present during the reaction. After 2 h in drug-free medium, rucaparib-induced PARP inhibition was maintained at 92.3 ± 4.3%, but was much less with talazoparib (58.6 ± 5.0%), pamiparib (56.0 ± 4.5%) olaparib (48.3 ± 19.8%), and niraparib (37.3 ± 11.6%). PARP inhibition in rucaparib-treated cells was maintained for 72 h in drug-free medium (77.7 ± 12.3%). This sustained PARP inhibition was not observed with the other PARPis. PARP inhibition was only 12.3 ± 5.2% and 12.5 ± 4.9% 72 h after talazoparib and pamiparib, respectively, and undetectable with olaparib and niraparib. Conclusion: Rucaparib is unique in its ability to cause persistent PARP inhibition and it is not a class effect. These data have clinical implications for the different uses of PARPi, as a single agent use to exploit HRR defects vs. chemo and radiosensitization. View Full-Text
Keywords: PARP-1 PARP-1
MDPI and ACS Style

Smith, H.L.; Mukhopadhyay, A.; Drew, Y.; Willmore, E.; Curtin, N. Differences in Durability of PARP Inhibition by PARP Inhibitors in Ovarian Cancer Cells. Med. Sci. Forum 2021, 3, 11. https://doi.org/10.3390/IECC2021-09194

AMA Style

Smith HL, Mukhopadhyay A, Drew Y, Willmore E, Curtin N. Differences in Durability of PARP Inhibition by PARP Inhibitors in Ovarian Cancer Cells. Medical Sciences Forum. 2021; 3(1):11. https://doi.org/10.3390/IECC2021-09194

Chicago/Turabian Style

Smith, Hannah L., Asima Mukhopadhyay, Yvette Drew, Elaine Willmore, and Nicola Curtin. 2021. "Differences in Durability of PARP Inhibition by PARP Inhibitors in Ovarian Cancer Cells" Medical Sciences Forum 3, no. 1: 11. https://doi.org/10.3390/IECC2021-09194

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