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Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells

文献类型：期刊论文

作者Li, Jing-qiu2,3; Wu, Xian2; Gan, Lu1; Yang, Xiang-liang2; Miao, Ze-hong3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2017-12
卷号38期号:12页码:1642-1654
关键词hepatocellular carcinoma hypoxia 5-fluorouracil sorafenib drug resistance
ISSN号1671-4083
DOI10.1038/aps.2017.79
文献子类Article
英文摘要Hepatocellular carcinoma (HCC) is one of the most refractory cancers. The mechanisms by which hypoxia further aggravates therapeutic responses of advanced HCC to anticancer drugs remain to be clarified. Here, we report that hypoxia (1% O2) caused 2.55-489.7-fold resistance to 6 anticancer drugs (sorafenib, 5-fluorouracil [5-FU], gemcitabine, cisplatin, adriamycin and 6-thioguanine) in 3 HCC cell lines (BEL-7402, HepG2 and SMMC-7721). Among the 6 drugs, sorafenib, the sole one approved for HCC therapy, inhibited proliferation with little influence from hypoxia and displayed the smallest variation among the 3 HCC cell lines tested. By contrast, the inhibition of proliferation by 5-FU, which has been extensively tested in clinical trials but has not been approved for HCC therapy, was severely affected by hypoxia and showed a large variation among these cell lines. In 5-FU-treated HCC cells, hypoxia reduced the levels of basal thymidylate synthase (TS) and functional TS, leading to decreased dTMP synthesis and DNA replication. Hypoxia also affected the accumulation of FdUTP and its misincorporation into DNA. Consequently, both single-strand breaks and double-strand breaks in DNA were reduced, although hypoxia also inhibited DNA repair. In 5-FU-treated HCC cells, hypoxia further abated S-phase arrest, alleviated the loss of mitochondrial membrane potential, diminished the activation of caspases, and finally resulted in reduced induction of apoptosis. Thus, hypoxia induces universal but differential drug resistance. The extensive impacts of hypoxia on the anticancer mechanisms of 5-FU contributes to its hypoxia-induced resistance in HCC cells. We propose that hypoxiainduced drug resistance and interference of hypoxia with anticancer mechanisms could be used as candidate biomarkers in selecting and/ or developing anticancer drugs for improving HCC therapy.
WOS关键词ADVANCED HEPATOCELLULAR-CARCINOMA ; GEMCITABINE PLUS OXALIPLATIN ; PHASE-II ; LIVER-CANCER ; TUMOR-CELLS ; DNA-DAMAGE ; SORAFENIB ; COMBINATION ; TRIAL ; MULTICENTER
资助项目National Basic Research Program of China[2012CB932500] ; National Basic Research Program of China[2012CB932502] ; National Natural Science Foundation of China[81372400] ; National Natural Science Foundation of China[81473171] ; National Natural Science Foundation of China[81373446] ; National Natural Science Foundation of China[81321092] ; Chinese Academy of Sciences[00000000] ; State Key Laboratory of Drug Research[00000000]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:6136213
WOS记录号WOS:000416938000006
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272368]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Yang, Xiang-liang; Miao, Ze-hong
作者单位1.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan 430074, Hubei, Peoples R China
2.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Natl Engn Res Ctr Nanomed, Wuhan 430074, Hubei, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Li, Jing-qiu,Wu, Xian,Gan, Lu,et al. Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells[J]. ACTA PHARMACOLOGICA SINICA,2017,38(12):1642-1654.
APA Li, Jing-qiu,Wu, Xian,Gan, Lu,Yang, Xiang-liang,&Miao, Ze-hong.(2017).Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells.ACTA PHARMACOLOGICA SINICA,38(12),1642-1654.
MLA Li, Jing-qiu,et al."Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells".ACTA PHARMACOLOGICA SINICA 38.12(2017):1642-1654.

入库方式： OAI收割

来源：上海药物研究所

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