Long-acting beta2-adrenergic formoterol and salmeterol induce the apoptosis of B-chronic lymphocytic leukaemia cells.
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 beta2-adrenergic compounds, well known cAMP-inducing drugs, on the in vitro survival of leukaemia cells. In contrast to the short-acting beta2-mimetic (beta2Mim) salbutamol, a consistent pro-apoptotic effect was observed with the long-acting beta2Mim 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 beta-adrenergic receptor signalling or cAMP did not alter B-CLL apoptosis with beta2 Mimagents. Leukaemia cell apoptosis by beta2Mim 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 beta2Mim. These data show that long-acting beta2-adrenergic agents promote apoptotic leukaemia cell death through an adrenoreceptor- and cAMP-independent, Ca2+-dependent mechanism.
Mamani-Matsuda
Maria
M
Bone Marrow Transplantation Laboratory, Bordeaux 2 University, 146 Rue Léo Saignat, 33076 Bordeaux cedex, France.
Moynet
Daniel
D
Molimard
Mathieu
M
Ferry-Dumazet
Hélène
H
Marit
Gérald
G
Reiffers
Josy
J
Mossalayi
M Djavad
MD
Mossalayi
M Diavad
MD
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D000420:Albuterol / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000627:therapeutic use; D000242:Cyclic AMP / Q000032:analysis; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein
D000318:Adrenergic beta-Agonists; D000970:Antineoplastic Agents; C494826:BAX protein, human; D004983:Ethanolamines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D002699:Chlorambucil; D000242:Cyclic AMP; D014740:Vidarabine; C024352:fludarabine; D000420:Albuterol; D002118:Calcium; D000068759:Formoterol Fumarate