The multidrug resistance phenotype confers immunological resistance.
Multidrug resistance (MDR), which is due, in part, to the overexpression of P-glycoprotein, confers resistance to a variety of natural product chemotherapeutic agents such as daunorubicin, vincristine, and colchicine. RV+ cells are a P-glycoprotein overexpressing variant of the HL60 myeloid leukemia cell line. In addition to classic MDR, RV+ cells displayed relative resistance to complement-mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing. Complement resistance was reversed both by treatment with verapamil and with specific monoclonal antibodies (mAbs) capable of binding to P-glycoprotein and blocking its function. To further confirm that the resistance of RV+ cells was not a consequence of the selection of the cells on vincristine, a second system involving P-glycoprotein infectants was also investigated. K562 cells infected with the MDR1 gene, which were never selected on chemotherapeutic drugs, also displayed relative resistance to complement-mediated cytotoxicity. This MDR1 infection-induced resistance was also reversed by mAbs that bind to P-glycoprotein. Therefore, the MDR phenotype as mediated by P-glycoprotein provides resistance to complement-mediated cytotoxicity. The increased intracellular pH and the decreased membrane potential due to the MDR phenotype may result in abnormal membrane attack complex function. This observation may have implications for the possible mechanisms of action of P-glycoprotein and for a possible physiologic role for P-glycoprotein in protection against complement-mediated autolysis.
Weisburg
J H
JH
Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Curcio
M
M
Caron
P C
PC
Raghu
G
G
Mechetner
E B
EB
Roepe
P D
PD
Scheinberg
D A
DA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D002999:Clone Cells; D003078:Colchicine / Q000633:toxicity; D003602:Cytotoxicity, Immunologic; D003630:Daunorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000276:immunology*; D014644:Genetic Variation; D018922:HL-60 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010641:Phenotype; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D014750:Vincristine; D003078:Colchicine; D003630:Daunorubicin