A second target of benzamide riboside Dihydrofolate reductase

• Published in: Cancer biology & therapy Vol. 13; no. 13; pp. 1290 - 1298
• Main Authors: Roussel, Breton, Johnson-Farley, Nadine, Kerrigan, John E., Scotto, Kathleen W, Banerjee, Debabrata, Felczak, Krzysztof, Pankiewicz, Krzysztof W., Gounder, Murugesan, Lin, HongXia, Abali, Emine Ercikan, Bertino, Joseph R
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.11.2012; Landes Bioscience
• Subjects: Adenine Nucleotides - genetics; Adenine Nucleotides - metabolism; benzamide adenine dinucleotide; benzamide riboside; Benzamides - metabolism; Binding; Biology; Bioscience; Calcium; Cancer; CCRF-CEM; Cell; Cell Line, Tumor; Cycle; dihydrofolate reductase; Down-Regulation - drug effects; Drug Resistance, Neoplasm; Humans; IMP Dehydrogenase - antagonists & inhibitors; IMP Dehydrogenase - genetics; IMP Dehydrogenase - metabolism; Landes; leukemia; methotrexate; Methotrexate - pharmacology; Molecular Targeted Therapy; NADP - genetics; NADP - metabolism; nicotinamide adenine dinucleotide kinase; Nucleosides - pharmacology; Organogenesis; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proteins; Research Paper; Tetrahydrofolate Dehydrogenase - genetics; Tetrahydrofolate Dehydrogenase - metabolism
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.21786

Dihydrofolate reductase (DHFR) is an essential enzyme involved in de novo purine and thymidine biosynthesis. For several decades, selective inhibition of DHFR has proven to be a potent therapeutic approach in the treatment of various cancers including acute lymphoblastic leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, carcinoma of the breast, and head and neck cancer. Therapeutic success with DHFR inhibitor methotrexate (MTX) has been compromised in the clinic, which limits the success of MTX treatment by both acquired and intrinsic resistance mechanisms. We report that benzamide riboside (BR), via anabolism to benzamide adenine dinucleotide (BAD) known to potently inhibit inosine monophosphate dehydrogenase (IMPDH), also inhibits cell growth through a mechanism involving downregulation of DHFR protein. Evidence to support this second site of action of BR includes the finding that CCRF-CEM/R human T-cell lymphoblasic leukemia cells, resistant to MTX as a consequence of gene amplification and overexpression of DHFR, are more resistant to BR than are parental cells. Studies of the mechanism by which BR lowers DHFR showed that BR, through its metabolite BAD, reduced NADP and NADPH cellular levels by inhibiting nicotinamide adenine dinucleotide kinase (NADK). As consequence of the lack of NADPH, DHFR was shown to be destabilized. We suggest that, inhibition of NADK is a new approach to downregulate DHFR and to inhibit cell growth.