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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-07-2339.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3674-3680
NEOPLASIA
Acadesine activates AMPK and induces apoptosis in B-cell chronic
lymphocytic leukemia cells but not in T lymphocytes
Clara Campàs,
José Manuel López,
Antonio F. Santidrián,
Montserrat Barragán,
Beatriz Bellosillo,
Dolors Colomer, and
Joan Gil
From the Unitat de Bioquímica, Departament de
Ciències Fisiològiques II, Universitat de Barcelona, Campus
de Bellvitge, E-08907 L'Hospitalet de Llobregat, Spain,
and Unitat d'Hematopatologia, Hospital Clínic, Institut
d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Barcelona, Spain.
Acadesine, 5-aminoimidazole-4-carboxamide (AICA) riboside, induced
apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in all
samples tested (n = 70). The half-maximal effective concentration
(EC50) for B-CLL cells was 380 ± 60 µM (n = 5). The
caspase inhibitor Z-VAD.fmk completely blocked acadesine-induced apoptosis, which involved the activation of caspase-3, -8, and -9 and
cytochrome c release. Incubation of B-CLL cells with
acadesine induced the phosphorylation of adenosine
monophosphate-activated protein kinase (AMPK), indicating that it is
activated by acadesine. Nitrobenzylthioinosine (NBTI), a nucleoside
transport inhibitor, 5-iodotubercidin, an inhibitor of adenosine
kinase, and adenosine completely inhibited acadesine-induced
apoptosis and AMPK phosphorylation, demonstrating that incorporation of
acadesine into the cell and its subsequent phosphorylation to AICA
ribotide (ZMP) are necessary to induce apoptosis. Inhibitors of
protein kinase A and mitogen-activated protein kinases did not protect
from acadesine-induced apoptosis in B-CLL cells. Moreover, acadesine
had no effect on p53 levels or phosphorylation, suggesting a
p53-independent mechanism in apoptosis triggering. Normal B lymphocytes
were as sensitive as B-CLL cells to acadesine-induced apoptosis.
However, T cells from patients with B-CLL were only slightly affected
by acadesine at doses up to 4 mM. AMPK phosphorylation did not occur in
T cells treated with acadesine. Intracellular levels of ZMP were higher in B-CLL cells than in T cells when both were treated with 0.5 mM
acadesine, suggesting that ZMP accumulation is necessary to activate
AMPK and induce apoptosis. These results suggest a new pathway
involving AMPK in the control of apoptosis in B-CLL cells and raise the
possibility of using acadesine in B-CLL treatment.
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