Multidrug resistance protein 7(MRP7,ABCC10)is a recently identified member of the ATP-binding cassette(ABC)transporter family,which adequately confers resistance to a diverse group of antineoplastic agents,including t...Multidrug resistance protein 7(MRP7,ABCC10)is a recently identified member of the ATP-binding cassette(ABC)transporter family,which adequately confers resistance to a diverse group of antineoplastic agents,including taxanes,vinca alkaloids and nucleoside analogs among others.Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas(NSCLC)compared to a normal healthy lung tissue.Recent studies revealed increased paclitaxel sensitivity in the Mrp7^(-/-)mouse model compared to their wild-type counterparts.This demonstrates that MRP7 is a key contributor in developing drug resistance.Recently our group reported that PD173074,a specific fibroblast growth factor receptor(FGFR)inhibitor,could significantly reverse P-glycoprotein-mediated MDR.However,whether PD173074 can interact with and inhibit other MRP members is unknown.In the present study,we investigated the ability of PD173074 to reverse MRP7-mediated MDR.We found that PD173074,at non-toxic concentration,could significantly increase the cellular sensitivity to MRP7 substrates.Mechanistic studies indicated that PD173074(1μmol/L)significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein,thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.展开更多
基金This work was supported by funds from NIH(No.1R15CA143701)St.John's University Research Seed Grant(No.579-1110-7002)to Z.S.Chen。
文摘Multidrug resistance protein 7(MRP7,ABCC10)is a recently identified member of the ATP-binding cassette(ABC)transporter family,which adequately confers resistance to a diverse group of antineoplastic agents,including taxanes,vinca alkaloids and nucleoside analogs among others.Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas(NSCLC)compared to a normal healthy lung tissue.Recent studies revealed increased paclitaxel sensitivity in the Mrp7^(-/-)mouse model compared to their wild-type counterparts.This demonstrates that MRP7 is a key contributor in developing drug resistance.Recently our group reported that PD173074,a specific fibroblast growth factor receptor(FGFR)inhibitor,could significantly reverse P-glycoprotein-mediated MDR.However,whether PD173074 can interact with and inhibit other MRP members is unknown.In the present study,we investigated the ability of PD173074 to reverse MRP7-mediated MDR.We found that PD173074,at non-toxic concentration,could significantly increase the cellular sensitivity to MRP7 substrates.Mechanistic studies indicated that PD173074(1μmol/L)significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein,thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
