ABCC10,also known as multidrug-resistant protein 7(MRP7),is the tenth member of the C subfamily of the ATP-binding cassette(ABC) superfamily.ABCC10 mediates multidrug resistance(MDR) in cancer cells by preventing the ...ABCC10,also known as multidrug-resistant protein 7(MRP7),is the tenth member of the C subfamily of the ATP-binding cassette(ABC) superfamily.ABCC10 mediates multidrug resistance(MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs.The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane.ABCC10 is a broad-specificity transporter of xenobiotics,including antitumor drugs,such as taxanes,epothilone B,vinca alkaloids,and cytarabine,as well as modulators of the estrogen pathway,such as tamoxifen.In recent years,ABCC10 inhibitors,including cepharanthine,lapatinib,erlotinib,nilotinib,imatinib,sildenafil,and vardenafil,have been reported to overcome ABCC10-mediated MDR.This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy,particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.展开更多
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supported by funds from the National Institute of Health (No.1R15CA143701)St.John's University Research Seed Grant (No.579-1110-7002) to Z.S.Chen
文摘ABCC10,also known as multidrug-resistant protein 7(MRP7),is the tenth member of the C subfamily of the ATP-binding cassette(ABC) superfamily.ABCC10 mediates multidrug resistance(MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs.The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane.ABCC10 is a broad-specificity transporter of xenobiotics,including antitumor drugs,such as taxanes,epothilone B,vinca alkaloids,and cytarabine,as well as modulators of the estrogen pathway,such as tamoxifen.In recent years,ABCC10 inhibitors,including cepharanthine,lapatinib,erlotinib,nilotinib,imatinib,sildenafil,and vardenafil,have been reported to overcome ABCC10-mediated MDR.This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy,particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.
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.
