Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent.

Détails

Ressource 1Télécharger: oncotarget-10-6723.pdf (2570.78 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_1BDC3B2158B7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent.
Périodique
Oncotarget
Auteur(s)
Cloux A.J., Aubry D., Heulot M., Widmann C., ElMokh O., Piacente F., Cea M., Nencioni A., Bellotti A., Bouzourène K., Pellegrin M., Mazzolai L., Duchosal M.A., Nahimana A.
ISSN
1949-2553 (Electronic)
ISSN-L
1949-2553
Statut éditorial
Publié
Date de publication
19/11/2019
Peer-reviewed
Oui
Volume
10
Numéro
62
Pages
6723-6738
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
APO866 is a small molecule drug that specifically inhibits nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Although, the antitumor activity of APO866 on various types of cancer models has been reported, information regarding mechanisms by which APO866 exerts its cytotoxic effects is not well defined. Here we show that APO866 induces a strong, time-dependent increase in highly reactive ROS, nitric oxide, cytosolic/mitochondrial superoxide anions and hydrogen peroxide. We provide evidence that APO866-mediated ROS production is modulated by PARP1 and triggers cell death through mitochondria depolarization and ATP loss. Genetic or pharmacologic inhibition of PARP1 prevented hydrogen peroxide accumulation, caspase activation, mitochondria depolarization, ATP loss and abrogates APO866-induced cell death, suggesting that the integrity of PARP1 status is required for cell death. Conversely, PARP1 activating drugs enhanced the anti-leukemia activity of APO866 Collectively, our studies show that APO866 induces ROS/RNS productions, which mediate its anti-leukemia effect. These results support testing new combinatorial strategies to enhance the antitumor activities of APO866.
Mots-clé
APO866/FK866, NAD, non-apoptotic death, parthanatos, tumor cell death
Pubmed
Open Access
Oui
Création de la notice
15/12/2019 17:51
Dernière modification de la notice
15/01/2021 7:08
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