Year: 2008
Type: article
Abstract: BACKGROUND: Rituximab 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 FINDINGS: Complement-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. CONCLUSIONS: Statins 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.
Source: PLoS Medicine
Authors: 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
Institutions: Medical University of Warsaw, Instytut Biologii Doświadczalnej im. Marcelego Nenckiego, Institute of Nuclear Physics, Polish Academy of Sciences, Genmab (Netherlands), International Institute of Molecular and Cell Biology, The Maria Sklodowska-Curie National Research Institute of Oncology, Instytut Hematologii i Transfuzjologi
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,460
OpenAlex ID: W1970516397