title: Anticancer agent CHS-828 inhibits cellular synthesis of NAD.
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.
authors.affiliation: Experimental Pathology Unit, National University Hospital, Biocentre, Building 2, 3rd Floor, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Uffe Høgh
authors.initials: UH
authors.lastname: Olesen
authors.forename: Mette Knak
authors.initials: MK
authors.lastname: Christensen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Björkling
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.forename: Peter Buhl
authors.initials: PB
authors.lastname: Jensen
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Søren Jensby
authors.initials: SJ
authors.lastname: Nielsen
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003486:Cyanides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D010880:Piperidines; D009243:NAD