期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 92, 期 -, 页码 164-172出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2017.08.001
关键词
Gastric cancer; Cisplatin; Drug resistance; PARP1; NHEJ pathway
资金
- National Natural Science Foundation of China [81520108027, 81521004, 91229125, 81370078]
- Natural Science Foundation of Jiangsu Higher Education Institutions [13KJA330001]
- Foundation of the Priority Academic Program Development (PAPD)
- Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Higher Education Institutions
Cisplatin (DDP) is the first line chemotherapeutic drug for several cancers, including gastric cancer (GC). Unfortunately, the rapid development of drug resistance remains a significant challenge for the clinical application of cisplatin. There is an urgent need to develop new strategies to overcome DDP resistance for cancer treatment. In this study, four types of human GC cells have been divided into naturally sensitive or naturally resistant categories according to their responses to cisplatin. PARP1 activity (poly (ADP-ribose), PAR) was found to be greatly increased in cisplatin-resistant GC cells. PARP1 inhibitors significantly enhanced cisplatin-induced DNA damage and apoptosis in the resistant GC cells via the inhibition of PAR. Mechanistically, PARP1 inhibitors suppress DNA-PKcs stability and reduce the capability of DNA double-strand break (DSB) repair via the NHEJ pathway. This was also verified in BGC823/DDP GC cells with acquired cisplatin resistance. In conclusion, we identified that PARP1 is a useful interceptive target in cisplatin-resistant GC cells. Our data provide a promising therapeutic strategy against cisplatin resistance in GC cells that has potential translational significance.
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