PT - JOURNAL ARTICLE AU - Hsieh, Yi-Ching AU - Tedeschi, Philip AU - AdeBisi Lawal, Rialnat AU - Banerjee, Debabrata AU - Scotto, Kathleen AU - Kerrigan, John E. AU - Lee, Kuo-Chieh AU - Johnson-Farley, Nadine AU - Bertino, Joseph R. AU - Abali, Emine Ercikan TI - Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs AID - 10.1124/mol.112.080218 DP - 2013 Feb 01 TA - Molecular Pharmacology PG - 339--353 VI - 83 IP - 2 4099 - http://molpharm.aspetjournals.org/content/83/2/339.short 4100 - http://molpharm.aspetjournals.org/content/83/2/339.full SO - Mol Pharmacol2013 Feb 01; 83 AB - 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.