Rituximab but not other anti-CD20 antibodies reverses multidrug resistance in 2 B lymphoma cell lines, blocks the activity of P-glycoprotein (P-gp), and induces P-gp to translocate out of lipid rafts.
The objective of this study was to investigate the ability of the anti-CD20 antibody, Rituximab (RTX), to inhibit the activity of P-glycoprotein (P-gp), and reverse multidrug resistance (MDR) in 2 P-gp/CD20 lymphoma cell lines. We determined whether RTX would chemosensitize the 2 P-gp cell lines in vitro, and inhibit the ability of the cells to efflux Rhodamine 123. One cell line was infected with an MDR1 vector and the other was generated by drug selection. We also determined whether RTX induced P-gp to translocate out of lipid rafts. RTX chemosensitized 2 different MDR cell lines, inhibited the activity of P-gp in both, and induced P-gp to translocate out of lipid rafts in the 1 cell line that was studied in greater detail. In contrast, 3 other anti-CD20 antibodies did not chemosensitize, inhibit the activity of P-gp, or induce it to translocate out of rafts, despite the fact that 1 antibody recognized the same epitope on CD20. Our results suggest that RTX can chemosensitize 2 CD20/P-gp cell lines in vitro by inhibiting the activity of the P-gp pump. The inhibition of P-gp activity correlated with the ability of RTX to induce P-gp to translocate out of lipid rafts. Although the mechanisms by which RTX effects P-gp translocation and activity are not yet known, they are not associated with acid-sphingomyelinase activation in raft microdomains, as described for the antiproliferative activity of RTX.
Ghetie
Maria-Ana
MA
The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-8576, USA.
Crank
Michelle
M
Kufert
Stephanie
S
Pop
Iliodora
I
Vitetta
Ellen
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D002051:Burkitt Lymphoma; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D021381:Protein Transport; D020112:Rhodamine 123; D000069283:Rituximab; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C494431:TMEM243 protein, human; D020112:Rhodamine 123; D000069283:Rituximab; D014750:Vincristine