Anticancer agent CHS-828 inhibits cellular synthesis of NAD

Malignant cells display increased demands for energy production and DNA repair. Nicotinamide adenine dinucleotide (NAD) is required for both processes and is also continuously degraded by cellular enzymes. Nicotinamide phosphoribosyltransferase (Nampt) is a crucial factor in the resynthesis of NAD,...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2008-03, Vol.367 (4), p.799-804
Main Authors: Olesen, Uffe Høgh, Christensen, Mette Knak, Björkling, Fredrik, Jäättelä, Marja, Jensen, Peter Buhl, Sehested, Maxwell, Nielsen, Søren Jensby
Format: Article
Language:English
Subjects:
Acrylamides - administration & dosage
Antineoplastic Agents - administration & dosage
Apoptosis - drug effects
Cancer
Cell Line, Tumor
CHS-828
Cyanides - administration & dosage
Dose-Response Relationship, Drug
FK866
Guanidines - administration & dosage
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - metabolism
Metabolism
NAD
NAD - metabolism
Nampt
PBEF
Piperidines - administration & dosage
Signal Transduction - drug effects
Visfatin
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Summary:Malignant cells display increased demands for energy production and DNA repair. Nicotinamide adenine dinucleotide (NAD) is required for both processes and is also continuously degraded by cellular enzymes. Nicotinamide phosphoribosyltransferase (Nampt) is a crucial factor in the resynthesis of NAD, and thus in cancer cell survival. Here, we establish the cytotoxic mechanism of action of the small molecule inhibitor CHS-828 to result from impaired synthesis of NAD. Initially, we detected cross-resistance in cells between CHS-828 and a known inhibitor of Nampt, FK866, a compound of a structurally different class. We then showed that nicotinamide protects against CHS-828-mediated cytotoxicity. Finally, we observed that treatment with CHS-828 depletes cellular NAD levels in sensitive cancer cells. In conclusion, these results strongly suggest that, like FK866, CHS-828 kills cancer cells by depleting NAD.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2008.01.019