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• W2005454910 abstract "Abstract Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD + synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD + pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β -lapachone ( β -lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β -Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD + consumption. Synergy with FK866+ β -lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD + synthesis while increasing NAD + consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P) + depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ -calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD + -Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD + synthesis and β -lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD + pools in cancer cells to sensitize them to ROS-mediated cell death by β -lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors." @default.
• W2005454910 created "2016-06-24" @default.
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• W2005454910 date "2015-01-15" @default.
• W2005454910 modified "2023-10-16" @default.
• W2005454910 title "NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone" @default.
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• W2005454910 doi "https://doi.org/10.1038/cddis.2014.564" @default.
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