Beta 2-adrenergic Formoterol and Salmeterol Induce CLL Apoptosis

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British Journal of Haematology

Volume 124 Issue 2 Page 141 - January 2004

doi:10.1046/j.1365-2141.2003.04746.x

research paper

Long-acting Beta 2-adrenergic formoterol and salmeterol induce the

apoptosis of B-chronic lymphocytic Leukaemia cells

Mamani-Matsuda1, Moynet2, Mathieu Molimard3, Hélène

Ferry-Dumazet1, Gérald Marit1, Josy Reiffers1 and M. Diavad

Mossalayi2

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 Beta 2-

adrenergic compounds, well known cAMP-inducing drugs, on the in vitro

survival of leukaemia cells. In contrast to the short-acting Beta 2-

mimetic (B2Mim) salbutamol, a consistent pro-apoptotic effect was

observed with the long-acting B2Mim 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 B-adrenergic receptor signalling or cAMP did not alter B-

CLL apoptosis with 2 Mimagents. Leukaemia cell apoptosis by B2Mim

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 B2Mim.

These data show that long-acting 2-adrenergic agents promote

apoptotic leukaemia cell death through an adrenoreceptor- and cAMP-

independent, Ca2+-dependent mechanism.