NAD+salvage pathway in cancer metabolism and therapy.
Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, cell growth, and cell death. Many of these pathways are typically dysregulated in cancer cells, making NAD+an intriguing target for cancer therapeutics. NAD+is mainly synthesized by the NAD+salvage pathway in cancer cells, and not surprisingly, the pharmacological targeting of the NAD+salvage pathway causes cancer cell cytotoxicity in vitro and in vivo. Several studies have described the precise consequences of NAD+depletion on cancer biology, and have demonstrated that NAD+ depletion results in depletion of energy levels through lowered rates of glycolysis, reduced citric acid cycle activity, and decreased oxidative phosphorylation. Additionally, depletion of NAD+causes sensitization of cancer cells to oxidative damage by disruption of the anti-oxidant defense system, decreased cell proliferation, and initiation of cell death through manipulation of cell signaling pathways (e.g., SIRT1 and p53). Recently, studies have explored the effect of well-known cancer therapeutics in combination with pharmacological depletion of NAD+levels, and found in many cases a synergistic effect on cancer cell cytotoxicity. In this context, we will discuss the effects of NAD+salvage pathway inhibition on cancer cell biology and provide insight on this pathway as a novel anti-cancer therapeutic target.
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Barry E
BE
Kennedy
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Tanveer
T
Sharif
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Emma
E
Martell
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Cathleen
C
Dai
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Youra
Y
Kim
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Patrick W K
PW
Lee
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada; Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, NS, Canada. Electronic address: shashi.gujar@dal.ca.
Shashi A
SA
Gujar
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D009243:NAD / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase
Cancer; Energy metabolism; Nicotinamide adenine dinucleotide; Nicotinamide phosphoribosyltransferase