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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2220-2228
NEOPLASIA
Activation of the nitric oxide synthase pathway represents a key
component of tumor necrosis factor-related apoptosis-inducing
ligand-mediated cytotoxicity on hematologic malignancies
Paola Secchiero,
Arianna Gonelli,
Claudio Celeghini,
Prisco Mirandola,
Lia Guidotti,
Giuseppe Visani,
Silvano Capitani, and
Giorgio Zauli
From the Department of Morphology and Embryology, Human
Anatomy Section, University of Ferrara, Ferrara, Italy; Department of
Biomorphology, "G. D'Annunzio" University of Chieti, Chieti Scalo,
Italy; Institute of Histology and General Embryology, University of
Bologna, Bologna, Italy; "L.A. Seragnoli" Institute of Hematology
and Clinical Oncology, University of Bologna, Bologna, Italy; and
Department of Human Normal Morphology, University of Trieste, Trieste,
Italy.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand
(TRAIL) induced both cytotoxic (apoptosis) and cytostatic (cell cycle
perturbation) effects on the human myeloid K562 cell line. TRAIL
stimulated caspase 3 and nitric oxide synthase (NOS) activities, and
both pathways cooperate in mediating inhibition of K562
survival/growth. This was demonstrated by the ability of z-VAD-fmk, a
broad inhibitor of effector caspases, and
N-nitro-L-arginine methyl ester (L-NAME), an NOS
pharmacologic inhibitor, to completely (z-VAD-fmk) or partially (L-NAME) suppress the TRAIL-mediated inhibitory activity. Moreover, z-VAD-fmk was able to block TRAIL-mediated apoptosis and cell cycle
abnormalities and increase of NOS activity. The addition of the NO
donor sodium nitroprusside (SNP) to K562 cells reproduced the
cytostatic effect of TRAIL without inducing apoptosis. When TRAIL was
associated to SNP, a synergistic increase of apoptosis and inhibition
of clonogenic activity was observed in K562 cells as well as in other
myeloblastic (HEL, HL-60), lymphoblastic (Jurkat, SupT1), and multiple
myeloma (RPMI 8226) cell lines. Although SNP greatly augmented
TRAIL-mediated antileukemic activity also on primary leukemic blasts,
normal erythroid and granulocytic cells were less sensitive to the
cytotoxicity mediated by TRAIL with or without SNP. These data indicate
that TRAIL promotes cytotoxicity in leukemic cells by activating
effector caspases, which directly lead to apoptosis and stimulate NO
production, which mediates cell cycle abnormalities. Both mechanisms
seem to be essential for TRAIL-mediated cytotoxicity.
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