Statins impair antitumor effects of rituximab by inducing conformational changes of CD20

被引：120

作者：

Winiarska, Magdalena ^{[1
,2
]}

Bil, Jacek ^{[1
]}

Wilczek, Ewa ^{[3
]}

Wilczynski, Grzegorz M. ^{[4
]}

Lekka, Malgorzata ^{[5
]}

Engelberts, Patrick J. ^{[6
]}

Mackus, Wendy J. M. ^{[6
]}

Gorska, Elzbieta ^{[2
]}

Bojarski, Lukasz ^{[7
]}

Stoklosa, Tomasz ^{[1
]}

Nowis, Dominika ^{[1
]}

Kurzaj, Zuzanna ^{[1
]}

Makowski, Marcin ^{[1
]}

Glodkowska, Eliza ^{[1
]}

Issat, Tadeusz ^{[1
]}

Mrowka, Piotr ^{[1
]}

Lasek, Witold ^{[1
]}

Dabrowska-Iwanicka, Anna ^{[8
]}

Basak, Grzegorz W. ^{[9
]}

Wasik, Maria ^{[2
]}

Warzocha, Krzysztof ^{[10
]}

Sinski, Maciej ^{[11
]}

Gaciong, Zbigniew ^{[11
]}

Jakobisiak, Marek ^{[1
]}

Parren, Paul W. H. I. ^{[6
]}

Golab, Jakub ^{[1
]}

机构：

[1] Med Univ Warsaw, Ctr Biostruct Res, Dept Immunol, Warsaw, Poland

[2] Med Univ Warsaw, Dept Lab Diagnost & Clin Immunol, Warsaw, Poland

[3] Med Univ Warsaw, Ctr Biostruct Res, Dept Pathol, Warsaw, Poland

[4] M Nencki Inst Expt Biol, Lab Mol & Syst Neuromorphol, PL-02093 Warsaw, Poland

[5] Henryk Niewodniczanski Inst Nucl Phys, Dept Appl Spect, Krakow, Poland

[6] Genmab, Utrecht, Netherlands

[7] Int Inst Mol & Cell Biol, Lab Neurodegenerat, Warsaw, Poland

[8] Marie Sklodowska Curie Mem Canc Ctr, Dept Lymphoproliferat Dis, Warsaw, Poland

[9] Med Univ Warsaw, Dept Hematol Oncol & Internal Dis, Warsaw, Poland

[10] Inst Hematol & Transfus Med, Warsaw, Poland

[11] Med Univ Warsaw, Dept Internal Dis Hypertens & Vasc Dis, Warsaw, Poland

来源：

PLOS MEDICINE | 2008年 / 5卷 / 03期

关键词：

MONOCLONAL-ANTIBODIES; VASCULAR ENDOTHELIUM; MEMBRANE CHOLESTEROL; INDUCED EXPRESSION; CELL-SURVIVAL; LIPID RAFTS; LYMPHOMA; LOVASTATIN; THERAPY; PROTEIN;

D O I：

10.1371/journal.pmed.0050064

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 Cr-51 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 rituximabmediated 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.

引用

页码：0502 / 0517

页数：16

共 47 条

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Proapoptotic and antitumor activities of the HMG-CoA reductase inhibitor, lovastatin, against Dalton's Lymphoma Ascites tumor in mice [J].