TY - JOUR T1 - Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs JF - Molecular Pharmacology JO - Mol Pharmacol SP - 339 LP - 353 DO - 10.1124/mol.112.080218 VL - 83 IS - 2 AU - Yi-Ching Hsieh AU - Philip Tedeschi AU - Rialnat AdeBisi Lawal AU - Debabrata Banerjee AU - Kathleen Scotto AU - John E. Kerrigan AU - Kuo-Chieh Lee AU - Nadine Johnson-Farley AU - Joseph R. Bertino AU - Emine Ercikan Abali Y1 - 2013/02/01 UR - http://molpharm.aspetjournals.org/content/83/2/339.abstract N2 - 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. ER -