Induction of G₂/M Arrest by Berberine via Activation of PI3K/Akt and p38 in Human Chondrosarcoma Cell Line

Oncol Res. 2014;22(3):147-57. doi: 10.3727/096504015X14298122915583.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Berberine / pharmacology*
  • CDC2 Protein Kinase
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Chondrosarcoma / drug therapy
  • Chondrosarcoma / genetics*
  • Chromones / pharmacology
  • Cyclin B1 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinases / biosynthesis
  • Enzyme Activation / drug effects*
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Humans
  • Imidazoles / pharmacology
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology
  • Retinoblastoma Protein / biosynthesis
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Protein p53 / biosynthesis
  • Up-Regulation / drug effects
  • cdc25 Phosphatases / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Chromones
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Imidazoles
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Berberine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proto-Oncogene Proteins c-akt
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CDC25C protein, human
  • cdc25 Phosphatases
  • SB 203580