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Long‐acting β2‐adrenergic formoterol and salmeterol induce the apoptosis of B‐chronic lymphocytic Leukaemia cells
Author(s) -
MamaniMatsuda Maria,
Moynet Daniel,
Molimard Mathieu,
FerryDumazet Hélène,
Marit Gérald,
Reiffers Josy,
Diavad Mossalayi M.
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04746.x
Subject(s) - apoptosis , formoterol , chronic lymphocytic leukemia , fludarabine , programmed cell death , cyclic adenosine monophosphate , medicine , endocrinology , biology , cytokine , salmeterol , cancer research , immunology , receptor , leukemia , biochemistry , chemotherapy , budesonide , asthma , corticosteroid , cyclophosphamide
Summary B‐cell chronic lymphocytic leukaemia (B‐CLL) is a neoplastic disorder characterized by defective apoptosis, cell accumulation in G0/G1, and high expression of BCL2 oncogene. Intracellular cyclic adenosine monophosphate (cAMP) accumulation increases the chemosensitivity of B‐CLL cells in vitro and in vivo . In the present study, we investigated the effects of β2‐adrenergic compounds, well known cAMP‐inducing drugs, on the in vitro survival of leukaemia cells. In contrast to the short‐acting β2‐mimetic (β2Mim) salbutamol, a consistent pro‐apoptotic effect was observed with the long‐acting β2Mim salmeterol and formoterol. Normal B cells isolated from control donors were totally resistant to the above molecules. These compounds also increased chlorambucil‐ and fludarabine‐induced death of B‐CLL cells. Blockade of β‐adrenergic receptor signalling or cAMP did not alter B‐CLL apoptosis with β2 Mimagents. Leukaemia cell apoptosis by β2Mim correlated with an increase in calcium influx, decreased bcl‐2 protein and mRNA levels, increase in BAX gene expression and a marked rise in BCL2/BAX mRNA ratios. Interleukin‐4, a cytokine that increases bcl‐2 expression in B‐CLL cells, rescued leukaemia cell from apoptosis with β2Mim. These data show that long‐acting β2‐adrenergic agents promote apoptotic leukaemia cell death through an adrenoreceptor‐ and cAMP‐independent, Ca 2+ ‐dependent mechanism.