Characterisation of a navelbine-resistant bladder carcinoma cell line cross-resistant to taxoids.
A bladder carcinoma cell line (J82) was selected for resistance to the new vinca alkaloid navelbine. The resistance factor of the resistant subline (J82-NVB) to navelbine was 17. P-glycoprotein was not detected in the membrane of J82-NVB cells. The lack of cross-resistance to multidrug-resistant (MDR) drugs such as doxorubicin, epipodophyllotoxins and colchicine, the absence of increase in navelbine efflux and the fact that a reduced accumulation of the drug cannot account for the resistance level confirmed that the phenotype of resistance of J82-NVB cells is not a classical MDR phenotype. Moreover, verapamil did not reverse the resistance of J82-NVB cells. The cells were cross-resistant to vinca alkaloids and taxoids which share the same target protein: tubulin. Analysis of microtubules using immunofluorescence showed that disassembly of the microtubular network occurred for the same concentration of navelbine in sensitive and resistant cells. However, after treatment with a concentration of navelbine inducing depolymerisation in both sensitive and resistant cells, reassembly of the microtubular network was observed only in resistant cells. This study suggests that the mechanism of resistance of J82-NVB cells involves recovery from the inhibition of microtubule dynamics induced by drug treatment.
Debal
V
V
Laboratoire de Spectroscopie Biomoléculaire, GIBSA, U.F.R. de Pharmacie, Reims, France.
Allam
N
N
Morjani
H
H
Millot
J M
JM
Braguer
D
D
Breillout
F
F
Manfait
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002277:Carcinoma / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D066298:In Vitro Techniques; D008870:Microtubules / Q000648:ultrastructure; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000077235:Vinorelbine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014404:Tubulin; D014747:Vinblastine; D003513:Cycloheximide; D000077235:Vinorelbine