Sensitization of cells overexpressing multidrug-resistant proteins by pluronic P85.
OBJECTIVE
This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRPI 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.
Batrakova
Elena V
EV
College of Pharmacy, Department of Pharmaceutical Sciences, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
Li
Shu
S
Alakhov
Valery Yu
VY
Elmquist
William F
WF
Miller
Donald W
DW
Kabanov
Alexander V
AV
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D020442:Poloxamer / Q000494:pharmacology*; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology; D014783:Viscosity
D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D004317:Doxorubicin; D005978:Glutathione; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020442:Poloxamer; D014747:Vinblastine; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1