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Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion

文献类型：期刊论文

作者Guo, Ne1,2; Li, Meng-Zhu1,2; Wang, Li-Min1,2; Chen, Hua-Dong1,2; Song, Shan-Shan1; Miao, Ze-Hong1,2; He, Jin-Xue1,2
刊名CANCER BIOLOGY & THERAPY
出版日期2022-01-08
页码14
关键词Combination therapy PARP1 resistance CXCL3-ERK1/2 signaling migration and invasion
ISSN号1538-4047
DOI10.1080/15384047.2021.2024414
通讯作者Miao, Ze-Hong(zhmiao@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要PARP1 and Chk1 inhibitors have been shown to be synergistic in different cancer models in relatively short time treatment modes. However, the consequences of long-term/repeated treatments with the combinations in cancer models remain unclear. In this study, the synergistic cytotoxicity of their combinations in 8 tumor cell lines was confirmed in a 7-day exposure mode. Then, pancreatic Capan-1 cells were repeatedly treated with the PARP1 inhibitor olaparib, the Chk1 inhibitor rabusertib or their combination for 211-214 days, during which the changes in drug sensitivity were monitored at a 35-day interval. Unexpectedly, among the 3 treatment modes, the combination treatments resulted in the highest-grade resistance to Chk1 (similar to 14.6 fold) and PARP1 (similar to 420.2 fold) inhibitors, respectively. Consistently, G2/M arrest and apoptosis decreased significantly in the resulting resistant variants exposed to olaparib. All 3 resistant variants also unexpectedly obtained enhanced migratory and invasive capabilities. Moreover, the combination treatments resulted in increased migration and invasion than olaparib alone. The expression of 124 genes changed significantly in all the resistant variants. We further demonstrate that activating CXCL3-ERK1/2 signaling might contribute to the enhanced migratory capabilities rather than the acquired drug resistance. Our findings indicate that repeated treatments with the rabusertib/olaparib combination result in increased drug resistance and a more aggressive cell phenotype than those with either single agent, providing new clues for future clinical anticancer tests of PARP1 and Chk1 inhibitor combinations.
WOS关键词ANTICANCER ACTIVITY ; CANCER ; CXCL3 ; OVEREXPRESSION ; OPPORTUNITIES ; COMBINATION ; LETHALITY ; DISCOVERY ; EFFICACY ; DESIGN
资助项目National Natural Science Foundation of China[81773764] ; National Natural Science Foundation of China[82073865] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09301010] ; Chinese Academy of Sciences[29201731121100101] ; Chinese Academy of Sciences[XDA12020104] ; Chinese Academy of Sciences[XDA12020109] ; Chinese Academy of Sciences[CASIMM0120185003] ; Shanghai RisingStar Program[19QA1410900] ; State Key Laboratory of Drug Research ; SA-SIBS Scholarship Program
WOS研究方向Oncology
语种英语
WOS记录号WOS:000740578300001
出版者TAYLOR & FRANCIS INC
源URL[http://119.78.100.183/handle/2S10ELR8/300691]  
专题新药研究国家重点实验室
通讯作者Miao, Ze-Hong; He, Jin-Xue
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Ne,Li, Meng-Zhu,Wang, Li-Min,et al. Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion[J]. CANCER BIOLOGY & THERAPY,2022:14.
APA Guo, Ne.,Li, Meng-Zhu.,Wang, Li-Min.,Chen, Hua-Dong.,Song, Shan-Shan.,...&He, Jin-Xue.(2022).Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion.CANCER BIOLOGY & THERAPY,14.
MLA Guo, Ne,et al."Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion".CANCER BIOLOGY & THERAPY (2022):14.

入库方式： OAI收割

来源：上海药物研究所

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