Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent
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Anne-Julie Cloux1, Dominique Aubry1, Mathieu Heulot3, Christian Widmann3, Oussama ElMokh1, Francesco Piacente4, Michele Cea4, Alessio Nencioni4, Axel Bellotti1, Karima Bouzourène5, Maxime Pellegrin5, Lucia Mazzolai5, Michel A. Duchosal1,2 and Aimable Nahimana1
1 Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland
2 Service of Hematology, University Hospital of Lausanne, Lausanne, Switzerland
3 Department of Physiology, University of Lausanne, Lausanne, Switzerland
4 Department of Internal Medicine, University of Genoa, Genoa, Italy
5 Division of Angiology, Heart and Vessel Department, Lausanne University Hospital, Lausanne, Switzerland
|Aimable Nahimana,||email:||[email protected]|
Keywords: tumor cell death; parthanatos; non-apoptotic death; APO866/FK866; NAD
Received: March 19, 2019 Accepted: November 07, 2019 Published: November 19, 2019
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.
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