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

Details

Serval ID
serval:BIB_1BDC3B2158B7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent.
Journal
Oncotarget
Author(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
Publication state
Published
Issued date
19/11/2019
Peer-reviewed
Oui
Volume
10
Number
62
Pages
6723-6738
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
APO866/FK866, NAD, non-apoptotic death, parthanatos, tumor cell death
Pubmed
Open Access
Yes
Create date
15/12/2019 17:51
Last modification date
09/05/2020 5:26
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