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-over-expressing 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.
Curtin
N J
NJ
Cancer Research Unit, University of Newcastle upon Tyne, Medical School, U.K. n.j.curtin@newcastle.ac.uk
Turner
D P
DP
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002455:Cell Division; D004176:Dipyridamole / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004176:Dipyridamole; D004317:Doxorubicin; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010726:Phosphodiesterase Inhibitors