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Biochem Biophys Res Commun. 2008 Mar 21;367(4):799-804. doi: 10.1016/j.bbrc.2008.01.019. Epub 2008 Jan 15.

Anticancer agent CHS-828 inhibits cellular synthesis of NAD.

Author information

1
Experimental Pathology Unit, National University Hospital, Biocentre, Building 2, 3rd Floor, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark.

Abstract

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.

PMID:
18201551
DOI:
10.1016/j.bbrc.2008.01.019
[Indexed for MEDLINE]

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