PARP-1 inhibition with or without ionizing radiation confers reactive oxygen species-mediated cytotoxicity preferentially to cancer cells with mutant TP53.

ABSTRACT: Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1.22 to 2.27. Radiosensitization was correlated with the induction of potentially lethal DNA double-strand breaks (DSB) but not with RAD51 foci formation. The ability of olaparib to radiosensitize MIBC cells was linked to the extent of cell kill achieved wit

SUBMITTER: Liu Q 

PROVIDER: S-EPMC5970015 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature