Reversal of multidrug resistance-associated protein-mediated drug resistance in cultured human neuroblastoma cells by the quinolone antibiotic difloxacin.
BACKGROUND
We have recently shown that high-level expression of the multidrug resistance-associated protein (MRP) gene is a powerful independent predictor of poor outcome in neuroblastoma. The clinical implication of these findings is that MRP modulators may prove therapeutically useful.


METHODS
We therefore investigated the ability of difloxacin, a quinolone antimicrobial antibiotic, to increase drug cytotoxicity in unselected cultured human neuroblastoma cells. Drug cytotoxicity was determined using a microtiter assay in neuroblastoma cells expressing low (SH-EP), intermediate (NBL-S), or high [BE(2)-C] levels of MRP.


RESULTS
Difloxacin (50 microg/ml) increased sensitivity to the MRP substrates, vincristine, doxorubicin, daunorubicin, and potassium antimony tartrate to an extent directly proportional to their level of MRP expression. No change in the response to cisplatin, which is not a substrate for MRP, was observed in any of the cell lines.


CONCLUSIONS
The data demonstrate that difloxacin can reverse drug resistance in unselected human neuroblastoma cells and is therefore a potential candidate for future clinical trials.
Norris
M D
MD
Children's Cancer Institute Australia for Medical Research, Sydney Children's Hospital.
Madafiglio
J
J
Gilbert
J
J
Marshall
G M
GM
Haber
M
M
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000230:Adenocarcinoma / Q000473:pathology; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000633:toxicity; D000966:Antimony Potassium Tartrate / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D024841:Fluoroquinolones; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000890:Anti-Infective Agents; D000966:Antimony Potassium Tartrate; D002939:Ciprofloxacin; D002945:Cisplatin; D003630:Daunorubicin; D004317:Doxorubicin; D024841:Fluoroquinolones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014750:Vincristine; C047225:difloxacin