Extent and persistence of P-glycoprotein inhibition in multidrug-resistant P388 cells after exposure to resistance-modifying agents.

Abstract

The low daunomycin (DAU) retention in P388 cells displaying P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) can be increased by the presence of various resistance-modifying agents (RMAs). Taking the DAU retention restoration as an indicator of Pgp function inhibition and using a few RMAs, including SDZ PSC 833, SDZ 280-446, cyclosporin A (CsA) and verapamil, we compared different conditions of MDR cell exposure to the RMA. The 'co + post-RMA' treatments (RMA present during both DAU uptake and efflux phases) generally led to higher DAU retention levels than the 'co-RMA' treatments (RMA present during the DAU uptake phase only). The magnitude and persistence of Pgp function inhibition induced by the RMA was further examined by only pulsing the cells with the RMA and growing them in RMA-free medium before the DAU retention assay ('pre-RMA' treatment). While recovery of Pgp function was nearly complete within minutes after a pulse exposure to verapamil, this took increasing times with CsA, SDZ 280-446 and SDZ PSC 833, the latter RMA leaving traces of inhibition of Pgp function even 2 days after the pulse exposure of the MDR-P388 cells. The persistence of Pgp inhibition conferred by some RMAs being much longer than by others, this feature should be taken into account when designing chemotherapy protocols in the clinic.