The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers  

作　　者：William J.E.Frye Lyn M.Huff JoséM.González Dalmasy Paula Salazar Rachel M.Carter Ryan T.Gensler Dominic Esposito Robert W.Robey Suresh V.Ambudkar Michael M.Gottesman 

机构地区：[1]Laboratory of Cell Biology,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD 20892,USA [2]Protein Expression Laboratory,Frederick National Laboratory for Cancer Research,Leidos Biomedical Research,Inc,Frederick,MD 21704,USA

出　　处：《Cancer Drug Resistance》2023年第3期468-480,共13页癌症耐药（英文）

基　　金：This research was funded by the Intramural Research Program of the National Institutes of Health,the National Cancer Institute.

摘　　要：Aim:Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid peroxidation.Several small molecule ferroptosis inducers(FINs)have been reported,yet little information is available regarding their interaction with the ATP-binding cassette(ABC)transporters P-glycoprotein(P-gp,ABCB1)and ABCG2.We thus sought to characterize the interactions of FINs with P-gp and ABCG2,which may provide information regarding oral bioavailability and brain penetration and predict drug-drug interactions.Methods:Cytotoxicity assays with ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2 were used to determine the ability of the transporters to confer resistance to FINs;confirmatory studies were performed in OVCAR8 and NCI/ADR-RES cells.The ability of FINs to inhibit P-gp or ABCG2 was determined using the fluorescent substrates rhodamine 123 or purpuin-18,respectively.Results:P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin.P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1.The FINs ML-162,GPX inhibitor 26a,and PACMA31 at 10µM were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells.GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells.Conclusion:Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain.The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

关 键 词：Ferroptosis drug resistance P-GLYCOPROTEIN ABCG2 

分 类 号：R730.2[医药卫生—肿瘤]