Reversal of multidrug resistance by methoxypolyethylene glycol-block-polycaprolactone diblock copolymers through the inhibition of P-glycoprotein function.
Overexpression of P-glycoprotein (Pgp) is one of the major limitations in cancer chemotherapy. Previous work has shown that amphiphilic diblock copolymers composed of methoxypolyethylene glycol-block-polycaprolactone (MePEG-b-PCL) diblock copolymers enhanced the cellular accumulation of Pgp substrates by modulating the function of this drug efflux transporter. The objective of this work was to determine whether MePEG-b-PCL diblock copolymers modulated Pgp function in multidrug resistant (MDR) cancer cells. The diblock copolymer enhanced the accumulation of various Pgp substrates in Pgp overexpressing MDR cells but did not influence substrate accumulation in non-Pgp expressing cells. Treatment of MDR cells with the diblock copolymer enhanced paclitaxel (ptx) and doxorubicin (dox) accumulation. Following uptake, ptx was rapidly effluxed from MDR cells whereas diblock copolymer treatment retained dox inside MDR cells. Treatment of MDR cells with the diblock copolymer reversed drug resistance to dox but not ptx. However, resistance to ptx was reversed by verapamil, which indicated that a sustained inhibition of Pgp was required for ptx to induce cytotoxicity in MDR cells. Taken together, these results highlight the potential of MePEG-b-PCL diblock copolymer to reverse drug resistance in MDR cancer cells through inhibition of Pgp function, making it a promising candidate for overcoming MDR.
Elamanchili
Praveen
P
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, Canada V6T 1Z3.
McEachern
Cyrus
C
Burt
Helen
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D011091:Polyesters / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014700:Verapamil / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011091:Polyesters; C016240:polycaprolactone; D011092:Polyethylene Glycols; D004317:Doxorubicin; C028210:monomethoxypolyethylene glycol; D014700:Verapamil; D017239:Paclitaxel