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.