Induction of autoantibodies to murine P-glycoprotein: Consequences on drug sensitivity in MDR cancer cells and on the expression of mdr genes in organs

Overexpression of the 170 kDa plasma membrane P-glycoprotein (P-gp) represents the most common MDR mechanism in chemotherapy. In this work, specific autoantibodies to fragments from extracellular loops 1, 2, and 4 of the murine MDR1 P-gp were elicited in mice using synthetic palmitoylated peptides r...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2007-06, Vol.358 (1), p.325-330
Main Authors: Perrin, Laura, Gatouillat, Grégory, Balasse, Emilie, Odot, Johann, Nicolau, Claude, Tosi, Pierre-François, Madoulet, Claudie
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - pharmacology
Antineoplastic Agents, Phytogenic - pharmacology
ATP Binding Cassette Transporter, Sub-Family B - biosynthesis
ATP-Binding Cassette Transporters - biosynthesis
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
ATP-Binding Cassette, Sub-Family B, Member 1 - immunology
Autoantibodies
Autoantibodies - biosynthesis
Cell Line, Tumor
Doxorubicin - pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Female
Genes, MDR
Liposomes
Mice
Multidrug resistance
Organ Specificity
P-glycoprotein
Peptides
Peptides - immunology
Vaccination
Vinblastine - pharmacology
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Summary:Overexpression of the 170 kDa plasma membrane P-glycoprotein (P-gp) represents the most common MDR mechanism in chemotherapy. In this work, specific autoantibodies to fragments from extracellular loops 1, 2, and 4 of the murine MDR1 P-gp were elicited in mice using synthetic palmitoylated peptides reconstituted in liposomes and alum. The highest IgG level was observed after the third immunization and the immune response against lipopeptides was still detected more than 200 days after immunizations. Immunocytochemichal studies revealed that these antibodies were specific for P-gp. When incubated with P-gp-expressing MDR cell lines, serum from immunized mice restored sensitivity to either doxorubicin or vinblastine, or had no effect in a cell type specific manner, suggesting that several mechanisms may occur in the establishment of the MDR phenotype. The expression of mdr1 and mdr3 genes was unchanged in organs from mice immunized with palmitoylpeptides grafted on liposomes. These results suggest that the induction of autoantibodies to P-gp is a safe strategy to overcome MDR in cancer chemotherapy.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2007.04.117