Induction of apoptosis in MDR1 expressing cells by daunorubicin with combinations of suboptimal concentrations of P-glycoprotein modulators

The application of most agents with the capacity to reverse multidrug resis tance (MDR) via modulation of the multidrug transporter P-glycoprotein (Pgp ) was shown to be associated with toxic side-effects. For this reason, we h ave investigated the effect of combinations of suboptimal concentrations of Pgp blockers on the induction of apoptosis and growth arrest in daunorubic in (D) treated, MDRI gene transfected cells. We used verapamil, PSC833 and Cremophor EL as Pgp modulators, which affect the function of Pgp by differe nt mechanisms. Treatment of NIH3T3/MDR1 cells with combinations of suboptim al concentrations of Pgp modulators in the presence of D caused apoptosis a nd G(2) arrest to the same extent as optimal concentrations of singly used blockers. We conclude that combinations of suboptimal concentrations of Pgp modulators may cause effective sensitization of resistant tumor cells, and at the same time, may avoid the frequently observed toxic effects experien ced in clinical trials with a single modifier applied at the optimal dose. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.