Difloxacin reverses multidrug-resistance in p388 adr cells via a mechanism independent of p-glycoprotein and without correcting drug transport or subcellular drug distribution.

In this study, we have examined in vitro chemosensitizing activity of difloxacin, a quinolone antimicrobial agent, in multidrug resistant murine leukemia P388/ADR cell line that overexpresses P-glycoprotein and exhibits decreased accumulation of anthracyclines and vincristine. Difloxacin, in a concentration-dependent manner, increased the sensitivity of P388/ADR cells to daunorubicin, adriamycin and vincristine without correcting the altered drug accumulation and subcellular distribution of daunorubicin. Furthermore, difloxacin had no significant effect on intracellular accumulation of rhodamine 123 dye, a substrate for P-glycoprotein. In addition, difloxacin increased the sensitivity of drug sensitive parental P388 cells to vincristine. Taken together these data suggest that difloxacin reverses MDR by a mechanism independent of P-glycoprotein. The chemosensitizing effect of difloxacin was observed at clinically achievable plasma concentrations. These data suggest that difloxacin is an effective chemosensitizer of multidrug resistant tumor cells and is a potential candidate for clinical use to reverse MDR.