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

Eur J Cancer. 1999 Jun;35(6):1020-6. doi: 10.1016/s0959-8049(99)00038-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Cell Division
  • Dipyridamole / therapeutic use*
  • Doxorubicin / therapeutic use
  • Drug Resistance, Neoplasm
  • Etoposide / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Multidrug Resistance-Associated Proteins
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Tumor Cells, Cultured

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Phosphodiesterase Inhibitors
  • Dipyridamole
  • Etoposide
  • Doxorubicin