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. © 2001 Cancer Research Campaign http://www.bjcancer.com

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

“…However, such a system raises the problem of the integrity of the drug and the persistence of its cytotoxic activity (2). In addition, it was shown that block copolymer micelles decrease intracellular ATP levels together with reducing ATPase activity of P-glycoprotein (22,59). In all cases, a physical interaction between the structure of the nanocarrier and the efflux transporter itself has been excluded.…”

Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

“…Of particular note is the evidence of antitumour activity of SP1049C in doxorubicin-resistant tumours (Batrakova et al, 1996) and in multiple drug resistance (MDR) cells (Venne et al, 1996;Alakhov et al, 1999). There appear to be several potential mechanisms, including inhibition of drug efflux transporters, abolishment of drug sequestration in acidic compartments, inhibition of the glutathione (GSH)/glutathione (GST) detoxification system and reduction of ATP selectively in MDR cells (Venne et al, 1996;Batrakova et al, 2001;Kabanov et al, 2002). In preclinical models, in vivo SP1049C was found to be superior to convential doxorubicin in all nine models tested.…”

Alteration of Genomic Responses to Doxorubicin and Prevention of MDR in Breast Cancer Cells by a Polymer Excipient: Pluronic P85

“…7 The monoclonal antibodies to Pgp, C219 (Dako Corp., Carpinteria, CA), were used at 1:100 dilution. The monoclonal antibodies to β-actin, anti-β-1-chicken integrin (Sigma, Inc.), were used at 1:200 dilution.…”

“…8 In addition Pluronic induces intracellular ATP depletion in MDR cells thus depriving these cells from the source of energy necessary for the function of Pgp and other cellular defense mechanisms. 7 The synergy between these two effects results in the strong chemosensitization of MDR tumors. The use of Pluronic in chemotherapy of the MDR tumors has reached clinical evaluation stages.…”