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, Giorgio Zauli

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2220-2228
Number of pages9
JournalBlood
Volume98
Issue number7
DOIs
Publication statusPublished - Oct 1 2001

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TNF-Related Apoptosis-Inducing Ligand
Hematologic Neoplasms
Cytotoxicity
Nitric Oxide Synthase
Tumor Necrosis Factor-alpha
Chemical activation
Apoptosis
Ligands
Nitroprusside
Cells
K562 Cells
Effector Caspases
Cell Cycle
NG-Nitroarginine Methyl Ester
Cytostatic Agents
Cell Line
Arginine
Erythroid Cells
Myeloid Cells
Multiple Myeloma

ASJC Scopus subject areas

  • Hematology

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Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies. / Secchiero, Paola; Gonelli, Arianna; Celeghini, Claudio; Mirandola, Prisco; Guidotti, Lia; Visani, Giuseppe; Capitani, Silvano; Zauli, Giorgio.

In: Blood, Vol. 98, No. 7, 01.10.2001, p. 2220-2228.

Research output: Contribution to journalArticle

Secchiero, Paola ; Gonelli, Arianna ; Celeghini, Claudio ; Mirandola, Prisco ; Guidotti, Lia ; Visani, Giuseppe ; Capitani, Silvano ; Zauli, Giorgio. / Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies. In: Blood. 2001 ; Vol. 98, No. 7. pp. 2220-2228.
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