Immunization with liposome-anchored pegylated peptides modulates doxorubicin sensitivity in P-glycoprotein-expressing P388 cells.
The clinical use of chemotherapy in cancer treatment is limited by the occurrence of multidrug resistance (MDR) associated with the overexpression of membrane transporters, one of the best known is P-glycoprotein (Pgp), that actively expels drugs out of tumor cells. To overcome Pgp-mediated MDR, synthetic peptides corresponding to fragments from extracellular loops 1, 2 and 4 of the murine Pgp were coupled to polyethylene glycol-distearoylphosphatidylethanolamine and inserted into empty or monophosphoryl lipid A-containing liposomes. This formulation elicited specific antibodies which blocked Pgp-mediated efflux of doxorubicin, resulting in increased intracellular drug accumulation and subsequent potentiation of the cytotoxic effect of doxorubicin on multidrug-resistant P388 (P388R) cells. Previous immunizations with MDR1 peptides improved the efficiency of chemotherapy against P388R cells in vivo, with an increase of 83% of mice survival time. Overall, these results suggest that this approach can modulate Pgp activity by blocking drug efflux and may have clinical relevance as an alternative strategy to toxic chemosensitizers in drug-resistant cancer therapy.
Gatouillat
Grégory
G
Laboratory of Biochemistry, IFR53, Faculty of Pharmacy, 51 rue Cognacq-Jay, 51096 Reims cedex, France.
Odot
Johann
J
Balasse
Emilie
E
Nicolau
Claude
C
Tosi
Pierre-François
PF
Hickman
David T
DT
López-Deber
María Pilar
MP
Madoulet
Claudie
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D005260:Female; D005434:Flow Cytometry; D007114:Immunization / Q000379:methods*; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011092:Polyethylene Glycols / Q000737:chemistry; D016019:Survival Analysis; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D008081:Liposomes; D010455:Peptides; D022223:Vaccines, Subunit; D011092:Polyethylene Glycols; D004317:Doxorubicin