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 ...Continue Reading
Differential protein S-thiolation of glyceraldehyde-3-phosphate dehydrogenase isoenzymes influences sensitivity to oxidative stress.
H2O2-induced block of glycolysis as an active ADP-ribosylation reaction protecting cells from apoptosis
Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells
Development of beta-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
Calcium-dependent modulation of poly(ADP-ribose) polymerase-1 alters cellular metabolism and DNA repair
An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone
The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor
Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of ARQ 501 (beta-lapachone) in plasma and tumors from nu/nu mouse xenografts
The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies
Oxidative modifications of glyceraldehyde-3-phosphate dehydrogenase play a key role in its multiple cellular functions
The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors
Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data
Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of β-lapachone for pancreatic cancer therapy
Expression patterns of nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase in human malignant lymphomas
β-lapachone significantly increases the effect of ionizing radiation to cause mitochondrial apoptosis via JNK activation in cancer cells
An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis
Lung cancer signature biomarkers: tissue specific semantic similarity based clustering of digital differential display (DDD) data
Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, in human cancer cells: metabolic basis and potential clinical implications.
18F]FLT and [18F]FDG PET for non-invasive treatment monitoring of the nicotinamide phosphoribosyltransferase inhibitor APO866 in human xenografts
Nicotinamide preferentially protects glycolysis in dermal fibroblasts under oxidative stress conditions
Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers
Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors
Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models
Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers
PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death
β-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells
Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption
Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone
Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone
Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation
NAMPT inhibition synergizes with NQO1-targeting agents in inducing apoptotic cell death in non-small cell lung cancer cells
Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1
Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma
Amelioration of Huntington's disease phenotypes by Beta-Lapachone is associated with increases in Sirt1 expression, CREB phosphorylation and PGC-1α deacetylation
Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP
High doses of sodium tungstate can promote mitochondrial dysfunction and oxidative stress in isolated mitochondria
Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia.
Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway
Inflammatory processes in obesity: focus on endothelial dysfunction and the role of adipokines as inflammatory mediators
The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism
Phase 1 study of ARQ 761, a β-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis
Targeting Base Excision Repair in Cancer: NQO1-Bioactivatable Drugs Improve Tumor Selectivity and Reduce Treatment Toxicity Through Radiosensitization of Human Cancer
Mesoporous Silica Nanoparticle-Based Combination of NQO1 Inhibitor and 5-Fluorouracil for Potent Antitumor Effect Against Head and Neck Squamous Cell Carcinoma (HNSCC)
Synthesis of quinones with highlighted biological applications: A critical update on the strategies towards bioactive compounds with emphasis on lapachones
A comprehensive review on β-lapachone: Mechanisms, structural modifications, and therapeutic potentials.
DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition
Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway.
Application of cation-π interactions in enzyme-substrate binding: Design, synthesis, biological evaluation, and molecular dynamics insights of novel hydrophilic substrates for NQO1.
Cancer Metabolism: Therapeutic Targets
Targeting the mechanisms by which cancer cells acquire energy for metabolic needs is a therapeutic target. Discover the latest research on cancer metabolism and therapeutic targets.
In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.
Apoptosis in Cancer
Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.
Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis