title: Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion.
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.
authors.affiliation: College of Pharmacy, Department of Pharmaceutical Sciences, Nebraska Medical Center, 986025, Omaha, NE, 68198-6025, USA
authors.forename: E V
authors.initials: EV
authors.lastname: Batrakova
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: W F
authors.initials: WF
authors.lastname: Elmquist
authors.forename: D W
authors.initials: DW
authors.lastname: Miller
authors.forename: V Y
authors.initials: VY
authors.lastname: Alakhov
authors.forename: A V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000098:blood supply; D002196:Capillaries / Q000166:cytology; D002417:Cattle; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000166:cytology; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D007624:KB Cells / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011060:Poloxalene / Q000494:pharmacology*; D013552:Swine; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; C422648:pluronic block copolymer p85; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D011060:Poloxalene; D000251:Adenosine Triphosphatases