The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia

被引：10

作者：

Manzoni, Delphine ^{[1
,2
]}

Catallo, Regine ^{[1
]}

Chebel, Amel ^{[1
]}

Baseggio, Lucile ^{[1
,2
]}

Michallet, Anne-Sophie ^{[3
]}

Roualdes, Olivier ^{[1
,2
]}

Magaud, Jean-Pierre ^{[2
]}

Salles, Gilles ^{[1
,3
]}

Ffrench, Martine ^{[1
,2
,3
]}

机构：

[1] Univ Lyon 1, Lab Proliferat Indolentes B, Fac Med Lyon Sud, CNRS UMR 5239,ENS,HCL, F-69622 Villeurbanne, France

[2] Ctr Hosp Lyon Sud, HCL, Hematol Lab, Pierre Benite, France

[3] Ctr Hosp Lyon Sud, HCL, Dept Hematol, Pierre Benite, France

来源：

LEUKEMIA RESEARCH | 2016年 / 47卷

关键词：

Lymphoid B-cells; Chronic lymphocytic leukemia; ibrutinib; Dexamethasone; Cell proliferation; DNA damage; BRUTONS TYROSINE KINASE; DNA-DAMAGE; EXPRESSION; APOPTOSIS; ACTIVATION; SENSITIVITY; PCI-32765; PROTEINS; CYCLE; MCL-1;

D O I：

10.1016/j.leukres.2016.05.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment. Copyright (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：1 / 7

页数：7

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