Dipyridamole-mediated reversal of multidrug resistance in MRP over-expressing human lung carcinoma cells in vitro

Expression of the multidrug resistance-associated protein (MRP) is widespread in human malignancies, high levels are associated with poor prognosis and may be responsible for intrinsic and radiotherapy-induced chemoresistance. In this study, the nucleoside transport inhibitor, dipyridamole (DP), was investigated as a chemosensitiser of MRP. In growth inhibition assays MRP-overexpressing COR L23/R cells were 20 times more resistant to VP16 and doxorubicin compared with the parental COR L23/R human lung carcinoma cells. DP caused an approximately 8-fold sensitisation of the resistant cells and a 2-fold sensitisation of the parental cells. DP enhanced the accumulation of VP16 1.5 to 2-fold in the parental cells, but had only a modest effect on VP16 accumulation in the resistant cells. VP16 efflux was rapid in both cell lines. DP caused a modest and transient inhibition of the initial efflux in the resistant cells but not the parental cells. Incubation with DP caused a progressive decrease in GSH levels which was more rapid and profound in COR L23/R cells than in COR L23/P cells. Thus, chemosensitisation to VP16 by DP in MRP-overexpressing COR L23/R cells appears to be caused by depletion of cellular GSH rather than a direct effect of DP on MRP-mediated drug accumulation and efflux. (C), 1999 Elsevier Science Ltd. All rights reserved.