RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer.
Vinorelbine (Navelbine), an amphiphilic semisynthetic Vinca alkaloid, has displayed superior activity and decreased resistance in the treatment of advanced non-small cell lung cancer (NSCLC) compared with other members of its class. Recently, vinorelbine and cisplatin combination chemotherapy has been shown for the first time to confer a significant survival advantage in early-stage lung cancer after surgical therapy. The biological mechanisms underlying the differential response of NSCLC to cytocidal activity of vinorelbine have yet to be elucidated. Our recent findings indicate a role of RLIP76, a non-ATP binding cassette transport protein, in catalyzing the ATP-dependent efflux of structurally and functionally unrelated chemotherapeutic agents such as doxorubicin and vinblastine in NSCLC. Present studies were conducted to assess whether RLIP76 mediates vinorelbine transport and resistance. Here we show that RLIP76 catalyzes the transport of vinorelbine in a saturable manner with respect to vinorelbine (K(m) 75 nmol/L) and ATP (K(m) = 3.4 mmol/L). Three-fold overexpression of RLIP76 in NSCLC and SCLC confers increased resistance to cytotoxicity. RLIP76 overexpression causes a sustained intracellular decrease in vinorelbine concentration because of increased efflux, and anti-RLIP76 antibodies sensitize lung cancer cells to vinorelbine by inhibiting its efflux. These studies for the first time show that RLIP76 mediates vinorelbine transport and is capable of conferring drug accumulation defect and resistance to lung cancer cells.
Stuckler
David
D
Department of Chemistry and Biochemistry, University of Texas at Arlington, 502 Yates Street, Arlington, TX 76019-0065, USA.
Singhal
Jyotsana
J
Singhal
Sharad S
SS
Yadav
Sushma
S
Awasthi
Yogesh C
YC
Awasthi
Sanjay
S
D018528:ATP-Binding Cassette Transporters / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D020690:GTPase-Activating Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077235:Vinorelbine
D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; D008081:Liposomes; C095637:RALBP1 protein, human; D014747:Vinblastine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D000077235:Vinorelbine