MRP1 modulation by PAK-104P: detection with technetium-99m-MIBI in cultured lung tumor cells.

Background: Resistance mediated by the MultiDrug Resistance protein (P-glycoprotein and MRP1), results in energy-dependent efflux of drugs and 99mTc-MIBI from the cells. The goal of our investigation was to evaluate the capacity of PAK-104P to lower multidrug resistance by decreasing substrate efflux.

Materials And Methods: 99mTc-MIBI accumulation was quantified in the leukaemia cell line which expresses the P-glycoprotein (K562/R) or not (K562/S) and the small lung cancer cell line which expresses MRP1 (GLC4/R) or not (GLC4/S). Three experimental protocols were used: 1). cells were treated with increasing concentrations of PAK-104P; 2). the plasma membrane potential was lowered; 3). intracellular reduced glutathione (GSH) was depleted.

Results: Exposure of cells to 5 microM PAK-104P affected 99mTc-MIBI accumulation as follow: 1). no effect on K562 cell lines; 2). increased 8-fold in GLC4/R; 3). enhanced in GLC4 after GSH concentration and transmembrane potential reduction.

Conclusion: Assessed by 99mTc-MIBI, PAK-104P modulated MRP1 activity by the decrease of intracellular GSH concentration.