1. The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia
- Author
-
Régine Catallo, Anne-Sophie Michallet, Olivier Roualdes, Jean-Pierre Magaud, Lucile Baseggio, Amel Chebel, Martine Ffrench, Gilles Salles, Delphine Manzoni, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Chronic lymphocytic leukemia ,Apoptosis ,Pharmacology ,Dexamethasone ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Tumor Cells, Cultured ,Lymphocytes ,Aged, 80 and over ,B-Lymphocytes ,Leukemia ,biology ,Cell Cycle ,Drug Synergism ,Hematology ,Cell cycle ,Middle Aged ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Ibrutinib ,Female ,France ,Antineoplastic Agents, Hormonal ,Patients ,Cells ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,Cyclin-dependent kinase ,Stress, Physiological ,medicine ,Bruton's tyrosine kinase ,Humans ,Aged ,Cell Proliferation ,therapy ,Cell growth ,business.industry ,Adenine ,Proteins ,Dna ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,Pyrimidines ,chemistry ,biology.protein ,Pyrazoles ,pathology ,business ,Laboratories ,DNA Damage - Abstract
International audience; 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
- Published
- 2016