ArticleMolecular pharmacology2013
Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- Oxidative Stress Induces the Phosphorylation of NADNeurochemical research · 2025Article
- Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.Nature metabolism · 2025Article
- Downregulation of NAD Kinase Expression in β-Cells Contributes to the Aging-Associated Decline in Glucose-Stimulated Insulin Secretion.Aging cell · 2025Article
- Homeostatic regulation of NAD(H) and NADP(H) in cells.Genes & diseases · 2024Review
- The Invasive AnemoneMetabolites · 2023Article
- (-)-Epigallocatechin Gallate is a Noncompetitive Inhibitor of NAD Kinase.ACS medicinal chemistry letters · 2022Article
- Single-Cell Chemical Proteomics (SCCP) Interrogates the Timing and Heterogeneity of Cancer Cell Commitment to Death.Analytical chemistry · 2022Article
- NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications.Signal transduction and targeted therapy · 2020Review
- Article
- Methotrexate impaired in-vivo matured mouse oocyte quality and the possible mechanisms.BMC molecular and cell biology · 2020Article
- NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview.Biomolecules · 2020Review
- NAD Analogs in Aid of Chemical Biology and Medicinal Chemistry.Molecules (Basel, Switzerland) · 2019Review
- DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents.Molecules (Basel, Switzerland) · 2019Review
- Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs.Medicinal research reviews · 2019Review
- Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP.The Journal of pharmacology and experimental therapeutics · 2018Article
- NAD Kinases: Metabolic Targets Controlling Redox Co-enzymes and Reducing Power Partitioning in Plant Stress and Development.Frontiers in plant science · 2018Review
- Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKα Activity.Scientific reports · 2017Article
- Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells.Frontiers in oncology · 2017Review
- Functional annotation of rare gene aberration drivers of pancreatic cancer.Nature communications · 2016Article
- Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy.Molecular pharmacology · 2015Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.