Abstract
Berberine is a clinically important natural isoquinoline alkaloid found in many medicinal herbs. Berberine has been shown to have many pharmacological effects including antimicrobial, antitumor, and anti-inflammatory activities. However, the effects and mechanism of action of berberine have not been studied in chondrosarcoma. Therefore, the effects of berberine on proliferation in a human chondrosarcoma cell line (HTB-94) were investigated. Berberine inhibited cell proliferation in a concentration-dependent manner. We also determined that inhibition of cell proliferation by berberine occurred via G2/M phase arrest in HTB-94 cells. Berberine induced cell cycle arrest at the G2/M phase by upregulation of p53 and p21 expression and suppressed cyclin B1, cyclin-dependent kinase 1 (cdc2), cdc25c, and phosphorylated retinoblastoma tumor-suppressor protein (pRb) expression. In addition, berberine stimulated phosphorylation of protein kinase B (Akt) and p38 kinase. Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt with LY294002 (LY) and p38 kinase with SB203580 (SB), respectively, decreased berberine-induced p53 and p21 expression and restored cell proliferation and expression of cyclin B1, cdc2, cdc25c, and pRb cell cycle progression proteins. These results suggest that berberine-induced inhibition of cell proliferation by cell cycle arrest at the G2/M phases was regulated through PI3K/Akt and p38 kinase pathways in HTB-94 chondrosarcoma cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Berberine / pharmacology*
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CDC2 Protein Kinase
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Chondrosarcoma / drug therapy
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Chondrosarcoma / genetics*
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Chromones / pharmacology
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Cyclin B1 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinases / biosynthesis
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Enzyme Activation / drug effects*
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G2 Phase Cell Cycle Checkpoints / drug effects*
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Humans
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Imidazoles / pharmacology
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / pharmacology
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Retinoblastoma Protein / biosynthesis
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Retinoblastoma Protein / metabolism
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Tumor Suppressor Protein p53 / biosynthesis
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Up-Regulation / drug effects
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cdc25 Phosphatases / biosynthesis
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Chromones
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Cyclin B1
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Cyclin-Dependent Kinase Inhibitor p21
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Imidazoles
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Pyridines
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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Berberine
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Proto-Oncogene Proteins c-akt
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CDC2 Protein Kinase
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CDK1 protein, human
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Cyclin-Dependent Kinases
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p38 Mitogen-Activated Protein Kinases
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CDC25C protein, human
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cdc25 Phosphatases
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SB 203580