title: Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs.
abstract: Dihydrofolate reductase (DHFR), because of its essential role in DNA synthesis, has been targeted for the treatment of a wide variety of human diseases, including cancer, autoimmune diseases, and infectious diseases. Methotrexate (MTX), a tight binding inhibitor of DHFR, is one of the most widely used drugs in cancer treatment and is especially effective in the treatment of acute lymphocytic leukemia, non-Hodgkin's lymphoma, and osteosarcoma. Limitations to its use in cancer include natural resistance and acquired resistance due to decreased cellular uptake and decreased retention due to impaired polyglutamylate formation and toxicity at higher doses. Here, we describe a novel mechanism to induce DHFR degradation through cofactor depletion in neoplastic cells by inhibition of NAD kinase, the only enzyme responsible for generating NADP, which is rapidly converted to NADPH by dehydrogenases/reductases. We identified an inhibitor of NAD kinase, thionicotinamide adenine dinucleotide phosphate (NADPS), which led to accelerated degradation of DHFR and to inhibition of cancer cell growth. Of importance, combination treatment of NADPS with MTX displayed significant synergy in a metastatic colon cancer cell line and was effective in a MTX-transport resistant leukemic cell line. We suggest that NAD kinase is a valid target for further inhibitor development for cancer treatment.
authors.affiliation: Departments of Pharmacology and Medicine, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Philip
authors.initials: P
authors.lastname: Tedeschi
authors.forename: Rialnat
authors.initials: R
authors.lastname: Adebisi Lawal
authors.forename: Debabrata
authors.initials: D
authors.lastname: Banerjee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scotto
authors.forename: John E
authors.initials: JE
authors.lastname: Kerrigan
authors.forename: Kuo-Chieh
authors.initials: KC
authors.lastname: Lee
authors.forename: Nadine
authors.initials: N
authors.lastname: Johnson-Farley
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Emine Ercikan
authors.initials: EE
authors.lastname: Abali
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D006207:Half-Life; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C015541:thionicotinamide adenine dinucleotide phosphate; D009536:Niacinamide; D009249:NADP; D013762:Tetrahydrofolate Dehydrogenase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021844:NAD kinase; D008727:Methotrexate