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.

@article{Chan2014SynergyBT,
  title={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.},
  author={Manuel Chan and Michel Gravel and Alexandre Bramoulle and G{\"a}elle Bridon and Daina Z. Avizonis and Gordon C. Shore and Anne Roulston},
  journal={Cancer research},
  year={2014},
  volume={74 21},
  pages={
          5948-54
        }
}
GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non-small cell lung… Expand
Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway
TLDR
A potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment is indicated, and administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ substantially attenuated the sensitization of NamPT inhibitor on TMZ antitumor action. Expand
NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone
TLDR
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. Expand
Molecular Effects of the Nampt Inhibitor FK866 on Leukemia Cells
TLDR
FK866 is a specific NAMPT inhibitor that lowers NAD+ concentration in cancer cells, reducing the activity of NAD+-dependent enzymes, impacting on ATP production and promoting cell death, and has completed a phase I trial in oncology with advanced solid tumors. Expand
Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration
TLDR
The discovery of a unique NAMPT inhibitor, LSN3154567, which is highly selective and has a potent and broad spectrum of anticancer activity and has the potential to be further developed clinically into a novel cancer therapeutic. Expand
Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation.
TLDR
The data demonstrates that the combination of a non-lethal dose of BL and low dose of APO866 optimizes significantly cell death on various PC lines over both compounds given separately and open new and promising combination in PC therapy. Expand
The role of extracellular and intracellular Nicotinamide phosphoribosyl-transferase in cancer: Diagnostic and therapeutic perspectives and challenges.
TLDR
The role of Nampt in cancer pathophysiology is explored as well as the mechanisms underlying the association between extracellular and intracellular Nampt, and malignancy are synopsized. Expand
APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells
TLDR
APO866 and Pgp inhibitors show a strong synergistic cooperation in leukemia cells, including acute myelogenous leukemia (AML) and B-cell chronic lymphocytic leukemia (B-CLL) samples, and further evaluations of the combination of these agents in clinical setting should be considered. Expand
New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology
TLDR
This review summarizes recent discoveries in NAD+/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents. Expand
Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy
TLDR
The most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NamPT targeting and the drawbacks so far encountered. Expand
Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer.
TLDR
A novel regulatory mechanism for Nampt in PDAC is revealed and it is suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment. Expand
...
1
2
3
4
...

References

SHOWING 1-10 OF 23 REFERENCES
The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors
TLDR
Findings indicating that GMX1778 is a potent and specific inhibitor of the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) indicate that cancer cells have a very high rate of NAD+ turnover, which makes NAD+ modulation an attractive target for anticancer therapy. Expand
Chemopotentiating effects of a novel NAD biosynthesis inhibitor, FK866, in combination with antineoplastic agents.
TLDR
The chemosensitizing effect of FK866 on cell death induced by antineoplastic drugs was particularly obvious in combination with substances like MNNG that cause NAD superset+ depletion per se. Expand
Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells
TLDR
It is confirmed that FK866 alone in neuroblastoma cells induces autophagy, and its effects are potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagic-related protein 7. Expand
Efficacy of Combining GMX1777 with Radiation Therapy for Human Head and Neck Carcinoma
TLDR
The data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Expand
Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777
TLDR
Results indicate that nicotinic acid is a potent antidote to treat GMX1777 overdose and support the design of an open-label, dose-escalation trial, in which patients with refractory solid tumors and lymphomas receive 24 h infusions of GMX 1777 as a single agent in 3-week cycles. Expand
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications
TLDR
The history of antifolates that led to the development of pemetrexed is traced and the unique properties of this agent are described, including its very rapid conversion to active polyglutamate derivatives in cells and its marked sensitivity to the level of physiologic folates in cells. Expand
Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors as therapeutics: rationales, controversies, clinical experience.
TLDR
The rationales for exploiting NAMPT inhibitors in cancer and inflammatory diseases are discussed and an overview of the preclinical and clinical studies in which these agents have been evaluated are provided. Expand
Overcoming temozolomide resistance in glioblastoma via dual inhibition of NAD+ biosynthesis and base excision repair.
TLDR
It is hypothesized that combined BER and NAD(+) biosynthesis inhibition will increase TMZ efficacy in glioblastoma cell lines greater than BER inhibition alone and significantly sensitizes glioma cells with elevated expression of MGMT and those deficient in MMR, two genotypes normally associated with TMZ resistance. Expand
Uracil–DNA Glycosylase Expression Determines Human Lung Cancer Cell Sensitivity to Pemetrexed
TLDR
UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value in experimental models, and Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG upregulation is protective. Expand
The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells*
TLDR
It is found that Nampt was the ratelimiting component in this mammalian NAD biosynthesis pathway and regulates the function of Sir2α and thereby plays an important role in controlling various biological events in mammals. Expand
...
1
2
3
...