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Low Dose Berberine Suppresses Cholangiocarcinoma Cell Progression as a Multi-Kinase Inhibitor
Sumalee Obchoei1, Marutpong Detarya2,3, Piyanard Boonnate4
1Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Songkhla 90110, Thailand.
Background:
Berberine (BBR), a natural isoquinoline alkaloid, possesses diverse pharmacological properties and anti-cancer effects that have been demonstrated in many in vitro and in vivo studies. In this study, the inhibitory effects and molecular mechanism of low dose BBR on EMT-induced cell migration, and invasion capability of cholangiocarcinoma (CCA) cell lines were demonstrated.
Methods:
The commercially available BBR chloride powder with purity ≥ 95% was used in this study. Effects of BBR on cell growth of two human CCA cell lines, KKU-213A and KKU-213B were measured using MTT assay. The progressive phenotypes-cell adhesion, migration, and invasion were evaluated using cell adhesion, wound healing, and Boyden chamber assays. Molecular docking analysis was performed to assess the possible binding mode of BBR against EGFR, Erk, STAT3 and Akt. The effects of BBR on the activations of EGF/EGFR and its downstream effectors were demonstrated using Western blotting.
Results:
BBR inhibited growth of CCA cells in a dose dependent manner. At sub-cytotoxic dose, BBR significantly inhibited cell adhesion, migration, invasion and decreased expression of vimentin, slug, and VEGFA of both CCA cell lines. Molecular docking suggested the simultaneous inhibitory activity of BBR on EGFR, Erk, STAT3 and Akt. The Western blot analyses revealed that upon the EGF/EGFR activation, BBR considerably attenuated the activations of EGFR, Erk, STAT3 and Akt.
Conclusion:
Low dose of BBR suppresses EMT and thus aggressiveness of CCA cells, in part by its multi-kinase inhibitor property on EGFR and its downstream pathways. BBR might be beneficial for therapy of human CCA.
Insights
Low dose berberine (BBR) inhibits cholangiocarcinoma (CCA) cell aggressiveness by suppressing epithelial-mesenchymal transition (EMT). BBR acts as a multi-kinase inhibitor, offering potential benefits for human CCA therapy.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Berberine (BBR) is a natural alkaloid with demonstrated anti-cancer properties.
- Cholangiocarcinoma (CCA) is an aggressive cancer where EMT promotes cell migration and invasion.
Purpose of the Study:
- To investigate the inhibitory effects of low-dose BBR on EMT-induced cell migration and invasion in CCA cell lines.
- To elucidate the molecular mechanisms underlying BBR's anti-cancer activity in CCA.
Main Methods:
- MTT assay for cell growth, adhesion, migration, and invasion assays (cell adhesion, wound healing, Boyden chamber).
- Molecular docking to assess BBR binding to EGFR, Erk, STAT3, and Akt.
- Western blotting to analyze EGFR and downstream effector activation.
Main Results:
- BBR inhibited CCA cell growth, adhesion, migration, and invasion in a dose-dependent manner.
- Low-dose BBR decreased vimentin, slug, and VEGFA expression.
- Molecular docking and Western blot confirmed BBR's inhibitory effect on EGFR, Erk, STAT3, and Akt pathways.
Conclusions:
- Low-dose BBR suppresses EMT and reduces CCA cell aggressiveness through multi-kinase inhibition.
- BBR shows potential as a therapeutic agent for human cholangiocarcinoma.
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