Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells.
The present study demonstrated that poly(oxypropylene) and poly(oxyethylene) block copolymer pluronic L61 (L61)-hypersensitized multidrug-resistant CHRC5 Chinese hamster ovary cells and MCF-7/ADR human breast carcinoma cells to the cytotoxic action of doxorubicin (Dox). CHRC5 and MCF-7/ADR cells manifested 290- and 700-fold increases, respectively, in their sensitivity to Dox/L61 formulation compared with free Dox. Their sensitive counterparts Aux-B1 and MCF-7 displayed only marginal or no increase at all in their response to Dox/L61. The study of the drug transport performed by flow cytometry showed that L61 enhanced the drug uptake and reduced the P-glycoprotein-mediated drug efflux. Visualization of Dox subcellular distribution in CHRC5 cells by fluorescent microscopy revealed that Dox was sequestered in cytoplasmic vesicles, whereas incubation of the cells with Dox/L61 altered the drug compartmentalization by releasing the drug from these vesicles and shifting it to the nucleus. These findings suggested that the hypersensitive response of multidrug-resistant cells to the action of Dox/L61 was caused by an increase in the drug accumulation and changes in its subcellular distribution.
Venne
A
A
Immunology Research Center, Institute Armand-Frappier, University of Quebec, Laval, Canada.
Li
S
S
Mandeville
R
R
Kabanov
A
A
Alakhov
V
V
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D011060:Poloxalene / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D011108:Polymers; D004317:Doxorubicin; D011060:Poloxalene