NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone

Z. Moore, G. Chakrabarti, X. Luo, A. Ali, Z. Hu, F. J. Fattah, R. Vemireddy, R. J. DeBerardinis, R. A. Brekken, D. A. Boothman

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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 (B85%) 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.

Original languageEnglish (US)
Article numbere1599
JournalCell Death and Disease
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2015

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Nicotinamide Phosphoribosyltransferase
Adenocarcinoma
Cell Death
NAD
Neoplasms
NADP
Oxidoreductases
Reactive Oxygen Species
Substrate Cycling
Poly Adenosine Diphosphate Ribose
Calpain
Poly(ADP-ribose) Polymerases
Glycolysis
Caspases
DNA Damage
Oxidation-Reduction

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

@article{537b1723b67c4274828c3347878733b4,
title = "NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone",
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 (B85{\%}) 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.",
author = "Z. Moore and G. Chakrabarti and X. Luo and A. Ali and Z. Hu and Fattah, {F. J.} and R. Vemireddy and DeBerardinis, {R. J.} and Brekken, {R. A.} and Boothman, {D. A.}",
year = "2015",
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language = "English (US)",
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T1 - NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone

AU - Moore, Z.

AU - Chakrabarti, G.

AU - Luo, X.

AU - Ali, A.

AU - Hu, Z.

AU - Fattah, F. J.

AU - Vemireddy, R.

AU - DeBerardinis, R. J.

AU - Brekken, R. A.

AU - Boothman, D. A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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 (B85%) 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.

AB - 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 (B85%) 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.

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