Abstract
This paper, for the first time, demonstrates that exposure of cells to the poly(ethylene oxide)-poly(propylene oxide) block copolymer, Pluronic P85, results in a substantial decrease in ATP levels selectively in MDR cells. Cells expressing high levels of functional P-glycoprotein (MCF-7/ADR, KBv; LLC-MDR1; Caco-2, bovine brain microvessel endothelial cells [BBMECs]) are highly responsive to Pluronic treatment, while cells with low levels of P-glycoprotein expression (MCF-7, KB, LLC-PK1, human umbilical vein endothelial cells [HUVECs] C2C12 myoblasts) are much less responsive to such treatment. Cytotoxicity studies suggest that Pluronic acts as a chemosensitizer and potentiates cytotoxic effects of doxorubicin in MDR cells. The ability of Pluronic to inhibit P-glycoprotein and sensitize MDR cells appears to be a result of ATP depletion. Because many mechanisms of drug resistance are energy dependent, a successful strategy for treating MDR cancer could be based on selective energy depletion in MDR cells. Therefore, the finding of the energy-depleting effects of Pluronic P85, in combination with its sensitization effects is of considerable theoretical and practical significance.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Adenosine Triphosphatases / metabolism
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Adenosine Triphosphate / deficiency
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Adenosine Triphosphate / metabolism
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Adenosine Triphosphate / pharmacology
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Animals
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Antibiotics, Antineoplastic / therapeutic use
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Biological Transport, Active / drug effects
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Brain / blood supply
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Capillaries / cytology
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Cattle
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Cell Line / drug effects
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Cell Line / metabolism
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Doxorubicin / pharmacology
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Drug Resistance, Multiple*
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Drug Resistance, Neoplasm*
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Endothelium, Vascular / cytology
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Energy Metabolism / drug effects*
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Humans
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KB Cells / drug effects
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KB Cells / metabolism
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Kinetics
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Neoplasms / pathology
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Poloxalene / pharmacology*
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Swine
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Umbilical Veins / cytology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibiotics, Antineoplastic
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Neoplasm Proteins
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pluronic block copolymer p85
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Doxorubicin
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Adenosine Triphosphate
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Poloxalene
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Adenosine Triphosphatases