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NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

1
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
2
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia
3
Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Sumedang 45363, Indonesia
4
Division of Oncology, Department of Orthopaedic Surgery, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia
5
Department of Pharmacology and Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(3), 358; https://doi.org/10.3390/biom10030358
Received: 27 January 2020 / Revised: 19 February 2020 / Accepted: 21 February 2020 / Published: 26 February 2020
(This article belongs to the Special Issue Nicotinamide in Health and Diseases)
Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers. View Full-Text
Keywords: NAMPT inhibitor; NADK inhibitor; dihydrofolate reductase; IDH mutation; NAD/NADPH pool NAMPT inhibitor; NADK inhibitor; dihydrofolate reductase; IDH mutation; NAD/NADPH pool
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Pramono, A.A.; Rather, G.M.; Herman, H.; Lestari, K.; Bertino, J.R. NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview. Biomolecules 2020, 10, 358.

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