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Characterisation of a navelbine-resistant bladder carcinoma cell line cross-resistant to taxoids
1Laboratoire de Spectroscopie Biomoléculaire, GIBSA, U.F.R. de Pharmacie, Reims, France.
Abstract:
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.
Insights
Bladder cancer cells developed resistance to navelbine, a vinca alkaloid. This resistance mechanism involves faster microtubule recovery after drug exposure, not typical multidrug resistance.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Navelbine is a vinca alkaloid used in chemotherapy.
- Drug resistance is a major challenge in cancer treatment.
- Understanding novel resistance mechanisms is crucial for improving therapeutic efficacy.
Purpose of the Study:
- To investigate the mechanism of navelbine resistance in bladder carcinoma J82 cells.
- To determine if the resistance phenotype is associated with classical multidrug resistance (MDR).
- To elucidate the role of microtubules in navelbine resistance.
Main Methods:
- Developed a navelbine-resistant bladder carcinoma cell line (J82-NVB).
- Assessed cross-resistance to other chemotherapy drugs and P-glycoprotein expression.
- Analyzed navelbine efflux, accumulation, and microtubule dynamics using immunofluorescence.
Main Results:
- J82-NVB cells exhibited 17-fold resistance to navelbine.
- No P-glycoprotein expression or classical MDR phenotype was observed.
- Cells showed cross-resistance to vinca alkaloids and taxoids, targeting tubulin.
- Resistant cells demonstrated faster reassembly of microtubules post-drug treatment.
Conclusions:
- Navelbine resistance in J82 cells is not a classical MDR phenotype.
- The mechanism involves an altered cellular response to microtubule disruption.
- Suggests a novel resistance mechanism related to microtubule dynamics recovery.