Oridonin induces G2/M cell cycle arrest and apoptosis through MAPK and p53 signaling pathways in HepG2 cells

Oncol Rep. 2010 Sep;24(3):647-51.

Abstract

Oridonin, the main active constituent of Isodon rubescen, has antihepatocarcinoma activity in experimental and clinical settings. The aims of the study were to explore the anticancer effect of oridonin in HepG2 cells and to investigate the underlying mechanisms. Results showed that oridonin treatment for 24 or 48 h resulted in a marked decrease in cell viability time- and dose-dependently. IC50 values were determined as 38.86 microM and 24.90 microM for 24-h and 48-h treatments, respectively. Flow cytometric analysis showed that a 24-h treatment of 40 microM oridonin induced G2/M cell cycle arrest and apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after DAPI staining. Immunoblot analysis demonstrated that oridonin treatment increased expression levels of p-JNK, p-p38, p-p53 and p21, elevated the level of cyclin B1/p-Cdc2 (Tyr15) complex, and inhibited the expression of p-ERK. Moreover, oridonin treatment activated caspase-9 and caspase-3. In conclusion, oridonin induced G2/M cell cycle arrest and apoptosis in HepG2 cells through MAPK and p53 pathways, which advances our understanding on the molecular mechanisms of oridonin in hepatocarcinoma management.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • CDC2 Protein Kinase
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / pathology*
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Cycle / drug effects*
  • Cell Division
  • Cell Survival / drug effects
  • Cyclin B / metabolism
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinases
  • Diterpenes, Kaurane / pharmacology*
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • G2 Phase
  • Hep G2 Cells
  • Humans
  • Inhibitory Concentration 50
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / pathology*
  • MAP Kinase Signaling System / drug effects*
  • Phosphorylation
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • CCNB1 protein, human
  • CDKN1A protein, human
  • Cyclin B
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Diterpenes, Kaurane
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • oridonin
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9