Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death

Cell Mol Life Sci. 2005 Apr;62(7-8):881-93. doi: 10.1007/s00018-005-5017-3.

Abstract

Beta-elemene is a novel anticancer drug, which was extracted from the ginger plant. However, the mechanism of action of beta-elemene in non-small-cell lung cancer (NSCLC) remains unknown. Here we show that beta-elemene had differential inhibitory effects on cell growth between NSCLC cell lines and lung fibroblast and bronchial epithelial cell lines. In addition, beta-elemene was found to arrest NSCLC cells at G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and phospho-Cdc2 (Thr-161) and increases in the levels of p27(kip1) and phospho-Cdc2 (Tyr-15). Moreover, beta-elemene reduced the expression of Cdc25C, which dephosphorylates/activates Cdc2, but enhanced the expression of the checkpoint kinase, Chk2, which phosphorylates/ inactivates Cdc25C. These findings suggest that the effect of beta-elemene on G2-M arrest in NSCLC cells is mediated partly by a Chk2-dependent mechanism. We also demonstrate that beta-elemene triggered apoptosis in NSCLC cells. Our results clearly show that beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly(ADP-ribose) polymerase in NSCLC cells. These data indicate that the effect of beta-elemene on lung cancer cell death may be through a mitochondrial release of the cytochrome c-mediated apoptotic pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects
  • CDC2 Protein Kinase / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Checkpoint Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, bcl-2 / physiology
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Sesquiterpenes / pharmacology*
  • Tumor Suppressor Proteins / metabolism
  • cdc25 Phosphatases / metabolism

Substances

  • Cell Cycle Proteins
  • Sesquiterpenes
  • Tumor Suppressor Proteins
  • beta-elemene
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDC25C protein, human
  • cdc25 Phosphatases
  • Caspases