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, 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.
Olesen
Uffe Høgh
UH
Experimental Pathology Unit, National University Hospital, Biocentre, Building 2, 3rd Floor, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark.
Christensen
Mette Knak
MK
Björkling
Fredrik
F
Jäättelä
Marja
M
Jensen
Peter Buhl
PB
Sehested
Maxwell
M
Nielsen
Søren Jensby
SJ
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*
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