ArticleJournal of experimental & clinical cancer research : CR2017
Cinchonine induces apoptosis of HeLa and A549 cells through targeting TRAF6.
Article in Journal of experimental & clinical cancer research : CR, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 44 citations in OpenAlex.
- Review
- Expression Profile of Metabotropic Glutamate Receptors in Lung Adenocarcinoma: GRM5 and Validation of Its Targeting Drug Cinchonine.International journal of molecular sciences · 2026Article
- The up-regulated expression level of deubiquitinating enzyme USP46 induces the apoptosis of A549 cells by TRAF6.Investigational new drugs · 2025Article
- Design, Synthesis, and Anti-Cancer Evaluation of Novel Water-Soluble Copper(I) Complexes Bearing Terpyridine and PTA Ligands.Molecules (Basel, Switzerland) · 2024Article
- Cinchonine: A Versatile Pharmacological Agent Derived from Natural Cinchona Alkaloids.Current topics in medicinal chemistry · 2024Review
- Tumor Necrosis Factor Receptor-Associated Factor 6 and Human Cancer: A Systematic Review of Mechanistic Insights, Functional Roles, and Therapeutic Potential.Journal of Cancer · 2024Review
- Hydroquinidine Demonstrates Remarkable Antineoplastic Effects on Non-small Cell Lung Cancer Cells.Current molecular medicine · 2024Article
- Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives.Pharmaceuticals (Basel, Switzerland) · 2023Article
- TRAF6 regulates autophagy and apoptosis of melanoma cells through c-Jun/ATG16L2 signaling pathway.MedComm · 2023Article
- A potent ion channel blocker, hydroquinidine, exhibits strong anti-cancer activity on colon, pancreatic, and hepatocellular cancer cells.Molecular biology reports · 2023Article
- Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.Drug design, development and therapy · 2023Article
- Hydroquinidine displays a significant anticarcinogenic activity in breast and ovarian cancer cells via inhibiting cell-cycle and stimulating apoptosis.Turkish journal of biology = Turk biyoloji dergisi · 2023Article
- The Role of TAK1 in RANKL-Induced Osteoclastogenesis.Calcified tissue international · 2022Review
- Benzoyl-xanthone derivative induces apoptosis in MCF-7 cells by binding TRAF6.Experimental and therapeutic medicine · 2022Article
- Inhibition of Porcine Epidemic Diarrhea Virus by CinchonineFrontiers in cellular and infection microbiology · 2022Article
- Antimicrobial Activity of Quasi-EnantiomericAntibiotics (Basel, Switzerland) · 2021Article
- Intracellular ethanol-mediated oxidation and apoptosis in HepG2/CYP2E1 cells impaired by two active peptides from seahorse (Food science & nutrition · 2021Article
- Antiviral, Antibacterial, Antifungal, and Cytotoxic Silver(I) BioMOF Assembled from 1,3,5-Triaza-7-Phoshaadamantane and Pyromellitic Acid.Molecules (Basel, Switzerland) · 2020Article
- HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6.International journal of molecular sciences · 2020Article
- Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer.BioMed research international · 2020Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCancer cells are known to over-express TRAF6 that is critical for both AKT and TAK1 activations. The Really Interesting New Gene (RING) domain of TRAF6 is believed to be responsible for the E3 ligase activity, ZINC fingers of TRAF6 provide critical support for the activity of the RING domain which is critical for both AKT and TAK1 activations.
methodsWe employed computational docking program to identify small molecules that could effectively and competitively bind with the RING domain of TRAF6, which is believed to be responsible for its E3 ligase activity. MTT assay and flow cytometry were employed to analyze apoptosis of cancer cells. Signaling pathways were detected using immunoprecipitation and western blotting, and immunofluorescence was pursued to assess the nature of binding of cinchonine to TRAF6. We also performed animal experiments to test effect of cinchonine in vivo.
resultsCinchonine, a naturally occurring Cinchona alkaloid identified from the docking study, could bind to TRAF6 in HeLa and A549 cells and induce apoptosis of these cancer cells. We found that AKT ubiquitination and phosphorylation as well as phosphorylation of TAK1 were decreased. These activities would lead to subsequent suppression anti-apoptotic protein Bcl-2, while elevating pro-apoptotic protein Bax. Immunofluorescence staining unambiguously demonstrated the binding of cinchonine specifically at the RING domain of TRAF6 in cells, thereby validating the computational modeling. Animal experiments showed that cinchonine could suppress tumor growth in mice without showing significant acute toxicity.
conclusionThese investigations suggest that through competitive binding with the RING domain of TRAF6, cinchonine could induce apoptosis via inhibiting AKT and TAK1 signaling pathways.
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