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NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview
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) an...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175141/ https://www.ncbi.nlm.nih.gov/pubmed/32111066 http://dx.doi.org/10.3390/biom10030358 |
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author | Pramono, Alvinsyah Adhityo Rather, Gulam M. Herman, Herry Lestari, Keri Bertino, Joseph R. |
author_facet | Pramono, Alvinsyah Adhityo Rather, Gulam M. Herman, Herry Lestari, Keri Bertino, Joseph R. |
author_sort | Pramono, Alvinsyah Adhityo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7175141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71751412020-04-28 NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview Pramono, Alvinsyah Adhityo Rather, Gulam M. Herman, Herry Lestari, Keri Bertino, Joseph R. Biomolecules Review 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. MDPI 2020-02-26 /pmc/articles/PMC7175141/ /pubmed/32111066 http://dx.doi.org/10.3390/biom10030358 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Pramono, Alvinsyah Adhityo Rather, Gulam M. Herman, Herry Lestari, Keri Bertino, Joseph R. NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview |
title | NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview |
title_full | NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview |
title_fullStr | NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview |
title_full_unstemmed | NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview |
title_short | NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview |
title_sort | nad- and nadph-contributing enzymes as therapeutic targets in cancer: an overview |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175141/ https://www.ncbi.nlm.nih.gov/pubmed/32111066 http://dx.doi.org/10.3390/biom10030358 |
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