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Deprecated: Implicit conversion from float 276.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Death+Dis 2015 ; 6 (1): e1599- Nephropedia Template TP
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NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by ?-lapachone #MMPMID25590809
Moore Z; Chakrabarti G; Luo X; Ali A; Hu Z; Fattah FJ; Vemireddy R; DeBerardinis RJ; Brekken RA; Boothman DA
Cell Death Dis 2015[Jan]; 6 (1): e1599- PMID25590809show ga
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, ?-lapachone (?-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. ?-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+?-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, ?-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 ?-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 ?-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors.