In vitro and in vivo cancer cell apoptosis triggered by competitive binding of Cinchona alkaloids to the RING domain of TRAF6

Biosci Biotechnol Biochem. 2019 Jun;83(6):1011-1026. doi: 10.1080/09168451.2018.1559030. Epub 2018 Dec 20.


TRAF6 is highly expressed in many tumors and plays an important role in the immune system. The aim of this study is to confirm anti-tumor activities of all naturally occurring Cinchona alkaloids that have been screened using computational docking program, and to validate the accuracy and specificity of the RING domain of TRAF6 as a potential anti-tumor target, and to explore their effect on the immune system. Results reported herein would demonstrate that Cinchona alkaloids could induce apoptosis in HeLa cells, inhibit the ubiquitination and phosphorylation of both AKT and TAK1, and up-regulate the ratio of Bax/Bcl-2. In addition, these compounds could induce apoptosis in vivo, and increase the secretion of TNF-α, IFN-γ, and IgG, while not significantly impacting the ratio of CD4+T/CD8+T. These investigations suggest that the RING domain of TRAF6 could serve as a de novo biological target for therapeutic treatment in cancers.

Keywords: alkaloids; RING domain of TRAF6; Tumor; apoptosi; immune.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Binding, Competitive
  • Cell Proliferation / drug effects
  • Cinchona Alkaloids / metabolism*
  • Cinchona Alkaloids / pharmacology*
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Immunoglobulin G / blood
  • In Situ Nick-End Labeling
  • Interferon-gamma / blood
  • Intracellular Signaling Peptides and Proteins
  • Lymphocyte Count
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Phosphorylation
  • Protein Domains*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • T-Lymphocytes / drug effects
  • TNF Receptor-Associated Factor 6 / chemistry
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Tumor Necrosis Factor-alpha / blood
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitination
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein / metabolism


  • BAX protein, human
  • Cinchona Alkaloids
  • Immunoglobulin G
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human
  • Tnf protein, mouse
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • Interferon-gamma
  • UBE2N protein, human
  • Ubiquitin-Conjugating Enzymes
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7