Cystine supplementation rebalances the redox homeostasis of microenvironment in non-small cell lung cancer cells and reverses their resistance to docetaxel  

作　　者：Si-jia Li Bei Cao Zhen-yao Lu Run-bin Sun Su-han Guo Yuan Xie Ji-ye Aa Guang-ji Wang 

机构地区：[1]Key Laboratory of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China [2]Phase I Clinical Trials Unit,Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China

出　　处：《Acta Pharmacologica Sinica》2021年第12期2132-2143,共12页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China,grant number 81773814;"Double First-Class"University project(CPU2018GF01);Leading Technology Foundation Research Project of Jiangsu province(BK20192005);Sanming Project of Medicine in Shenzhen(SZSM201801060).

摘　　要：Continuous docetaxel(DTX)treatment of non-small cell lung cancer induces development of drug resistance,but the mechanism is poorly understood.In this study we performed metabolomics analysis to characterize the metabolic patterns of sensitive and resistant A549 non-small cell lung cancer cells(A549/DTX cells).We showed that the sensitive and resistant A549 cells exhibited distinct metabolic phenotypes:the resistant cells were characterized by an altered microenvironment of redox homeostasis with reduced glutathione and elevated reactive oxygen species(ROS).DTX induction reprogrammed the metabolic phenotype of the sensitive cells,which acquired a phenotype similar to that of the resistant cells:it reduced cystine influx,inhibited glutathione biosynthesis,increased ROS and decreased glutathione/glutathione disulfide(GSH/GSSG);the genes involved in glutathione biosynthesis were dramatically depressed.Addition of the ROS-inducing agent Rosup(25,50μg/mL)significantly increased P-glycoprotein expression and reduced intracellular DTX in the sensitive A549 cells,which ultimately acquired a phenotype similar to that of the resistant cells.Supplementation of cystine(1.0 mM)significantly increased GSH synthesis,rebalanced the redox homeostasis of A549/DTX cells,and reversed DTX-induced upregulation of P-glycoprotein,and it markedly improved the effects of DTX and inhibited the growth of A549/DTX in vitro and in vivo.These results suggest that microenvironmental redox homeostasis plays a key role in the acquired resistance of A549 cancer cells to DTX.The enhancement of GSH synthesis by supplementary cystine is a promising strategy to reverse the resistance of tumor cells and has potential for translation in the clinic.

关 键 词：non-small cell lung cancer cells DOCETAXEL drug resistance metabolomics MICROENVIRONMENT redox homeostasis P-GLYCOPROTEIN CYSTINE Rosup NAC 

分 类 号：R734.2[医药卫生—肿瘤]