Jakub Golab and colleagues found that statins significantly decrease rituximab-mediated complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against B cell lymphoma cells

Basak, Grzegorz W

Bil, Jacek

Bojarski, Lukasz

Dabrowska-Iwanicka, Anna

Engelberts, Patrick J

Gaciong, Zbigniew

Glodkowska, Eliza

Golab, Jakub

Gorska, Elzbieta

Issat, Tadeusz

Jakobisiak, Marek

Kurzaj, Zuzanna

Lasek, Witold

Lekka, Malgorzata

Mackus, Wendy J. M

Makowski, Marcin

Mrowka, Piotr

Nowis, Dominika

Parren, Paul W. H. I

Sinski, Maciej

Stoklosa, Tomasz

Warzocha, Krzysztof

Wasik, Maria

Wilczek, Ewa

Wilczynski, Grzegorz M

Winiarska, Magdalena

English

PubMed

BackgroundRituximab is used in the treatment of CD20+ B cell lymphomas and other B cell lymphoproliferative disorders. Its clinical efficacy might be further improved by combinations with other drugs such as statins that inhibit cholesterol synthesis and show promising antilymphoma effects. The objective of this study was to evaluate the influence of statins on rituximab-induced killing of B cell lymphomas.Methods and findingsComplement-dependent cytotoxicity (CDC) was assessed by MTT and Alamar blue assays as well as trypan blue staining, and antibody-dependent cellular cytotoxicity (ADCC) was assessed by a 51Cr release assay. Statins were found to significantly decrease rituximab-mediated CDC and ADCC of B cell lymphoma cells. Incubation of B cell lymphoma cells with statins decreased CD20 immunostaining in flow cytometry studies but did not affect total cellular levels of CD20 as measured with RT-PCR and Western blotting. Similar effects are exerted by other cholesterol-depleting agents (methyl-beta-cyclodextrin and berberine), but not filipin III, indicating that the presence of plasma membrane cholesterol and not lipid rafts is required for rituximab-mediated CDC. Immunofluorescence microscopy using double staining with monoclonal antibodies (mAbs) directed against a conformational epitope and a linear cytoplasmic epitope revealed that CD20 is present in the plasma membrane in comparable amounts in control and statin-treated cells. Atomic force microscopy and limited proteolysis indicated that statins, through cholesterol depletion, induce conformational changes in CD20 that result in impaired binding of anti-CD20 mAb. An in vivo reduction of cholesterol induced by short-term treatment of five patients with hypercholesterolemia with atorvastatin resulted in reduced anti-CD20 binding to freshly isolated B cells.ConclusionsStatins were shown to interfere with both detection of CD20 and antilymphoma activity of rituximab. These studies have significant clinical implications, as impaired binding of mAbs to conformational epitopes of CD20 elicited by statins could delay diagnosis, postpone effective treatment, or impair anti-lymphoma activity of rituximab

Magdalena Winiarska

Jacek Bil

Ewa Wilczek

Grzegorz M Wilczynski

Malgorzata Lekka

Patrick J Engelberts

Wendy J M Mackus

Elzbieta Gorska

Lukasz Bojarski

Tomasz Stoklosa

Dominika Nowis

Zuzanna Kurzaj

Marcin Makowski

Eliza Glodkowska

Tadeusz Issat

Piotr Mrowka

Witold Lasek

Anna Dabrowska-Iwanicka

Grzegorz W Basak

Maria Wasik

Krzysztof Warzocha

Maciej Sinski

Zbigniew Gaciong

Marek Jakobisiak

Paul W H I Parren

Jakub Golab

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Statins Impair Antitumor Effects of Rituximab by Inducing Conformational Changes of CD20

Statins Impair Antitumor Effects of Rituximab by Inducing Conformational Changes of CD20

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