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 multid rug resistance-associated protein (MRP) gene is a powerful independent pred ictor of poor outcome in neuroblastoma. The clinical implication of these f indings is that MRP modulators may prove therapeutically useful. Procedure. We therefore investigated the ability of difloxacin, a quinolone antimicro bial antibiotic, to increase drug cytotoxicity in unselected cultured human neuroblastoma cells. Drug cytotoxicity was determined using a microtiter a ssay in neuroblastoma cells expressing low (SH-EP), intermediate (NBL-S), o r high [BE(2)-C] levels of MRP. Results. Difloxacin (50 mug/ml) increased s ensitivity to the MRP substrates, vincristine, doxorubicin, daunorubicin, a nd potassium antimony tartrate to an extent directly proportional to their level of MRP expression. No change in the response to cisplatin, which is n ot a substrate for MRP, was observed in any of the cell lines. Conclusions. The data demonstrate that difloxacin can reverse drug resistance in unsele cted human neuroblastoma cells and is therefore a potential candidate for f uture clinical trials. Med. Pediatr. Oncol. 36:177-180, 2001. (C) 2001 Wile y-Liss. Inc.