Purpose. This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRP1 and MRP2. Methods. Cell models included MRP1- and MRP2-transfected MDCKII cells as well as doxorubicin-selected COR-L23/R cells overexpressing MRP1. Effects of P85 on cellular accumulation and cytotoxicity of vinblastine and doxorubicin were determined. Mechanistic studies characterized the effects of P85 on ATP and reduced glutathione (GSH) intracellular levels as well as MRP ATPase and glutathione-S-transferase (GST) activities in these cells. Results. Considerable increases of vinblastine and doxorubicin accumulation in the cells overexpressing MRP1 and MRP2 in the presence of P85 were observed, although no statistically significant changes in drug accumulation in the parental cells were found. P85 treatment caused an inhibition of MRP ATPase activity. Furthermore, P85 induced ATP depletion in these cells similar to that previously reported for Pgp-overexpressing cells. In addition, reduction of GSH intracellular levels and decrease of GST activity were observed following P85 treatment. Finally, significant enhancement of cytotoxicity of vinblastine and doxorubicin by P85 in MRP-overexpressing cells was demonstrated. Conclusions. This study suggests that P85 can sensitize cells overexpressing MRP1 and MRP2, which could be useful for chemotherapy of cancers that display these resistant mechanisms.
Bibliographical noteFunding Information:
This study was supported by National Institutes of Health grant CA89225. We would like to thank Piet Borst (Netherlands Cancer Institute, Amsterdam, Netherlands) for kindly providing MRP-transfected cell lines and Dr. Kenneth Brouwer (Glaxo Wellcome, Inc., Research Triangle Park, NC, USA) for kindly providing GF120918.
Copyright 2008 Elsevier B.V., All rights reserved.