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 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.
Perrin
Laura
L
Laboratory of Biochemistry, EA 3796, IFR 53 Biomolécules, 51 rue Cognac-Jay, 51096 Reims Cedex, France.
Gatouillat
Grégory
G
Balasse
Emilie
E
Odot
Johann
J
Nicolau
Claude
C
Tosi
Pierre-François
PF
Madoulet
Claudie
C
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000276:immunology*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D019450:Genes, MDR; D008081:Liposomes; D051379:Mice; D009928:Organ Specificity; D010455:Peptides / Q000276:immunology; D014747:Vinblastine / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001323:Autoantibodies; D008081:Liposomes; D010455:Peptides; D014747:Vinblastine; D004317:Doxorubicin; C095122:multidrug resistance protein 3