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Oncogene v.37 no.21, 2018년, pp.2793 - 2805   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

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

Liu, Qi (Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Gheorghiu, Liliana (Department of Radiation Oncology, University of California, San Francisco, CA, USA ) ; Drumm, Michael (Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Clayman, Rebecca (Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Eidelman, Alec (Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Wszolek, Matthew F. (Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Olumi, Aria (Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Feldman, Adam (Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Wang, Meng (Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ) ; Marcar, Lynnette (Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical Sc ) ; Citrin, Deborah E. ; Wu, Chin-Lee ; Benes, Cyril H. ; Efstathiou, Jason A. ; Willers, Henning ;
  • 초록  

    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 with the drug alone. Unexpectedly, increased levels of reactive oxygen species (ROS) resulting from PARPi treatment were the cause of DSB throughout the cell cycle in vitro and in vivo. ROS originated from mitochondria and were required for the radiosensitizing effects of olaparib. Consistent with the role of TP53 in ROS regulation, loss of p53 function enhanced radiosensitization by olaparib in non-isogenic and isogenic cell line models and was associated with increased PARP-1 expression in bladder cancer cell lines and tumors. Impairment of ATM in addition to p53 loss resulted in an even more pronounced radiosensitization. In conclusion, ROS suppression by PARP-1 in MIBC is a potential therapeutic target either for PARPi combined with radiation or drug alone treatment. The TP53 and ATM genes, commonly mutated in MIBC and other cancers, are candidate biomarkers of PARPi-mediated radiosensitization.


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