A second target of benzamide riboside Dihydrofolate reductase

Breton Roussel, Nadine Johnson-Farley, John E. Kerrigan, Kathleen W. Scotto, Debabrata Banerjee, Krzysztof Felczak, Krzysztof W. Pankiewicz, Murugesan Gounder, Hongxia Lin, Emine Ercikan Abali, Joseph R. Bertino

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)1290-1298
Number of pages9
JournalCancer Biology and Therapy
Volume13
Issue number13
DOIs
StatePublished - Nov 2012

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute (RO1-CA08010).

Keywords

  • Benzamide adenine dinucleotide
  • Benzamide riboside
  • CCRF-CEM
  • Dihydrofolate reductase
  • Leukemia
  • Methotrexate
  • Nicotinamide adenine dinucleotide kinase

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