ArticleOncogene2014
Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 39 citations in OpenAlex.
- Helping Apo2L/TRAIL in the Battle: Synergistic Therapeutic Approaches for Cancer Therapies.International journal of molecular sciences · 2026Review
- NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy.Journal of experimental & clinical cancer research : CR · 2025Article
- RSL3 promotes PARP1 apoptotic functions by distinct mechanisms during ferroptosis.Cellular & molecular biology letters · 2025Article
- De novo pyrimidine biosynthesis inhibition synergizes with BCL-XNature communications · 2025Article
- GPX3-Mediated Oxidative Stress Affects Pyrimidine Metabolism Levels in Stomach Adenocarcinoma via the AMPK/mTOR Pathway.International journal of clinical practice · 2024Article
- Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library.ACS omega · 2023Article
- Nucleotide metabolism: a pan-cancer metabolic dependency.Nature reviews. Cancer · 2023Review
- Metabolic inhibitor screening identifies dihydrofolate reductase as an inducer of the tumor immune escape mediator CD24.Immunomedicine · 2022Article
- DHODH and cancer: promising prospects to be explored.Cancer & metabolism · 2021Review
- The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia.Cancers · 2021Article
- Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine.Frontiers in oncology · 2021Review
- On the Origin of ATP Synthesis in Cancer.iScience · 2020Review
- Dihydroorotate dehydrogenase inhibitors in SARS-CoV-2 infection.European journal of clinical investigation · 2020Article
- Review
- Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2019Article
- Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells.Cell metabolism · 2019Article
- Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.Journal of medicinal chemistry · 2018Article
- Inactivation/deficiency of DHODH induces cell cycle arrest and programed cell death in melanoma.Oncotarget · 2017Article
- Metabolomic Evidence for a Field Effect in Histologically Normal and Metaplastic Tissues in Patients with Esophageal Adenocarcinoma.Neoplasia (New York, N.Y.) · 2017Article
- Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent in selectively killing tumor cells. However, TRAIL monotherapy has not been successful as many cancer cells are resistant to TRAIL. Chemotherapeutic agents, such as doxorubicin have been shown to act synergistically with TRAIL, but the exact mechanisms of actions are poorly understood. In this study, we performed high-throughput small interfering RNA screening and genome-wide gene expression profiling on doxorubicin-treated U1690 cells to explore novel mechanisms underlying doxorubicin-TRAIL synergy. The screening and expression profiling results were integrated and dihydroorotate dehydrogenase (DHODH) was identified as a potential candidate. DHODH is the rate-limiting enzyme in the pyrimidine synthesis pathway, and its expression was downregulated by doxorubicin. We demonstrated that silencing of DHODH or inhibition of DHODH activity by brequinar dramatically increased the sensitivity of U1690 cells to TRAIL-induced apoptosis both in 2D and 3D cultures, and was accompanied by downregulation of c-FLIPL as well as by mitochondrial depolarization. In addition, uridine, an end product of the pyrimidine synthesis pathway was able to rescue the sensitization effects initiated by both brequinar and doxorubicin. Furthermore, several other cancer cell lines, LNCaP, MCF-7 and HT-29 were also shown to be sensitized to TRAIL by brequinar. Taken together, our findings have identified a novel protein target and its inhibitor, brequinar, as a potential agent in TRAIL-based combinatorial cancer therapy and highlighted for the first time the importance of mitochondrial DHODH enzyme and pyrimidine pathway in mediating TRAIL sensitization in cancer cells.
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Registered trials
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