期刊
FRONTIERS IN ONCOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.812264
关键词
BMN 673; high-grade serous ovarian cancer; PARP inhibitor; phenethyl isothiocyanate; reactive oxygen species
类别
资金
- Liaoning Revitalization Talents Program [XLYC2002043]
- Liaoning Provincial Key Research and Development Program [2020JH2/10300049]
- Dalian Leading Talents Fund [203598]
- Doctoral Foundation of Liaoning Province [2020-BS-188]
- National Natural Science Foundation of China [81172457]
- Natural Science Foundation of Liaoning Province [20170540234]
- Science and Technology Innovation Fund of Dalian Department of Science and Technology [2020JJ27SN079, 2021JJ12SN39]
This study demonstrates that oxidative stress sensitizes HGSOC cells to PARPi BMN 673 and that the combination of PEITC and BMN 673 enhances cytotoxic effects through ROS-mediated mechanisms. The PEITC/BMN 673 combination significantly inhibits the growth of HGSOC and cervical cancer, suggesting a potential novel therapeutic strategy for these cancers.
While PARP inhibitor (PARPi) therapies have shown promising results in the treatment of high-grade serous ovarian cancer (HGSOC) harboring homologous recombination deficiencies, primary resistance to PARPi frequently occurs and even initial responders may eventually become resistant. Therefore, the development of novel effective combinatorial strategies to treat HGSOC is urgently needed. Here, we report that H2O2-induced oxidative stress sensitized HGSOC cells to PARPi BMN 673. Furthermore, Phenethyl isothiocyanate (PEITC) as a ROS-inducing agent significantly enhanced the cytotoxic effects of BMN 673. Mechanistically, combined use of PEITC and BMN 673 resulted in ROS overproduction and accumulation, enhanced DNA damage, G2/M arrest and apoptosis, all of which were significantly reversed by the ROS scavenger N-Acetyl-L-cysteine. We also showed that while PEITC did not further enhance the ability of BMN 673 on PARP1 trapping in HGSOC cells, the therapeutic effects of the PEITC/BMN 673 combination were at least in part dependent on the presence of PARP1. Importantly, the PEITC/BMN 673 combination potently abrogated the growth of HGSOC tumor spheroids and patient-derived organoid models of HGSOC and cervical cancer. Our findings provide a basis for further investigation of the utility of PARPi combination regimen in HGSOC and cervical cancer through ROS-mediated mechanisms.
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