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

Lookup NU author(s): Professor Nicola Curtin, Dr David Turner

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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-overexpressing COR L231R cells were 20 times more resistant to VP16 and doxorubicin compared with the parental COR L231R 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 metadata

Author(s): Curtin, N.J., Turner, D.P.

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 1999

Volume: 35

Issue: 6

Pages: 1020-1026

Print publication date: 01/06/1999

ISSN (print): 0959-8049

ISSN (electronic): 1359-6349

URL: http://dx.doi.org/10.1016/S0959-8049(99)00038-6

DOI: 10.1016/S0959-8049(99)00038-6

PubMed id: 10533488


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