ArticleOncotarget2016
Inhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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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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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- A novel dihydroisoxazole derivative DHI9 suppresses colorectal cancer cell survival by inducing oxidative stress, DNA damage, and mitochondrial apoptosis while targeting Akt and Wnt/β-catenin signalling.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Highlighting the Therapeutic Potential of an Underexplored Target: Human Dihydroorotate Dehydrogenase in Cancer, Rheumatoid Arthritis and Sclerosis.Current topics in medicinal chemistry · 2026Review
- De novo pyrimidine biosynthesis inhibition synergizes with BCL-XNature communications · 2025Article
- Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis.Discover oncology · 2025Article
- Article
- Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma.Translational cancer research · 2023Article
- Teriflunomide - The common drug with underestimated oxygen - Dependent anticancer potential.Biochemistry and biophysics reports · 2021Article
- DHODH and cancer: promising prospects to be explored.Cancer & metabolism · 2021Review
- Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review.International immunopharmacology · 2021Review
- Epidermal Growth Factor Protects Against High Glucose-Induced Podocyte Injury Possibly via Modulation of Autophagy and PI3K/AKT/mTOR Signaling Pathway Through DNA Methylation.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Article
- Classification of Clear Cell Renal Cell Carcinoma based on Tumor Suppressor Genomic Profiling.Journal of Cancer · 2021Article
- Inhibition ofInternational journal of biological sciences · 2021Article
- Construction and Validation of Predictive Model to Identify Critical Genes Associated with Advanced Kidney Disease.International journal of genomics · 2020Article
- Leflunomide Inhibits Proliferation and Induces Apoptosis via Suppressing Autophagy and PI3K/Akt Signaling Pathway in Human Bladder Cancer Cells.Drug design, development and therapy · 2020Article
- Leflunomide Synergizes with Gemcitabine in Growth Inhibition of PC Cells and Impairs c-Myc Signaling through PIM Kinase Targeting.Molecular therapy oncolytics · 2019Article
- Article
- Prediction of key gene function in spinal muscular atrophy using guilt by association method based on network and gene ontology.Experimental and therapeutic medicine · 2019Article
- Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis.Emerging microbes & infections · 2018Article
- Leflunomide attenuates oxidative stress in fetal human lung endothelial cells via superoxide dismutase 2 and catalase.Biochemical and biophysical research communications · 2018Article
- Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates.Cell death & disease · 2018Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 μM induced S-phase arrest and autophagy. Higher doses of LEF (>50 μM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of β-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/β-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/β-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).
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