Antifungal therapy with itraconazole impairs the anti-lymphoma effects of rituximab by inhibiting recruitment of CD20 to cell surface lipid rafts.
Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to membrane microdomains. Here, we show that concomitant antifungal treatment with itraconazole impairs the rituximab anti-lymphoma effect both in vitro and in vivo. At the molecular level, recruitment of CD20 to lipid rafts is inhibited in the presence of itraconazole. Furthermore, calcium influx, which is crucial for rituximab-mediated cell death, was nearly completely abolished by itraconazole treatment. In contrast, the antifungal drug caspofungin did not inhibit CD20 recruitment to lipid rafts, nor did it affect calcium influx or the cytotoxic effect of rituximab. The finding that itraconazole also abolished the cytotoxic effects of other therapeutic antibodies directed against lipid raft-associated molecules (i.e., CD20 and CD52) but not those against the non-raft-associated molecule CD33 further supported our proposed mechanism of action. Our results argue that concomitant medications must be adjusted carefully to achieve optimal antitumor effects with monoclonal antibodies.
Ringshausen
Ingo
I
Third Medical Department and Department of Nuclear Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.
Feuerstacke
Yvonne
Y
Krainz
Philipp
P
den Hollander
Jürgen
J
Hermann
Ken
K
Buck
Andreas
A
Peschel
Christian
C
Meyer Zum Bueschenfelde
Christian
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000935:Antifungal Agents / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077336:Caspofungin; D004347:Drug Interactions; D054714:Echinocandins / Q000494:pharmacology; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D019169:Jurkat Cells; D055666:Lipopeptides; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000935:Antifungal Agents; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D054714:Echinocandins; D055666:Lipopeptides; D017964:Itraconazole; D000069283:Rituximab; D000077336:Caspofungin