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Int J Biochem Cell Biol. 2017 Nov;92:164-172. doi: 10.1016/j.biocel.2017.08.001. Epub 2017 Aug 4.

Inhibition of PARP1 activity enhances chemotherapeutic efficiency in cisplatin-resistant gastric cancer cells.

Author information

1
Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of the Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
2
Laboratory of Cancer Biology, Biomedical Research Center, Sir Runrun Shaw Hospital, Zhejiang University, Hangzhou, China.
3
Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of the Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: sywang@njmu.edu.cn.
4
Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of the Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: jwzhou@njmu.edu.cn.

Abstract

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.

KEYWORDS:

Cisplatin; Drug resistance; Gastric cancer; NHEJ pathway; PARP1

PMID:
28827033
DOI:
10.1016/j.biocel.2017.08.001
[Indexed for MEDLINE]

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