title: The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France; Hematology laboratory, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Manzoni
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France.
authors.forename: Régine
authors.initials: R
authors.lastname: Catallo
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France.
authors.forename: Amel
authors.initials: A
authors.lastname: Chebel
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France; Hematology laboratory, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Baseggio
authors.affiliation: Hematology department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Michallet
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France; Hematology laboratory, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Roualdes
authors.affiliation: Hematology laboratory, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Magaud
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France; Hematology department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Laboratory "Proliférations B indolentes", Université Claude Bernard Lyon 1, CNRS UMR 5239-Ecole Normale Supérieure (ENS)-Hospices Civil de Lyon (HCL), Faculté de Médecine Lyon Sud, France; Hematology laboratory, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France; Hematology department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL), France. Electronic address: ffrenchma@gmail.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Ffrench
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D003907:Dexamethasone; D000225:Adenine
keywords: Cell proliferation; Chronic lymphocytic leukemia; DNA damage; Dexamethasone; Ibrutinib; Lymphoid B-cells