Celastrol induces apoptosis in non-small-cell lung cancer A549 cells through activation of mitochondria- and Fas/FasL-mediated pathways

Toxicol In Vitro. 2011 Aug;25(5):1027-32. doi: 10.1016/j.tiv.2011.03.023. Epub 2011 Apr 3.

Abstract

Celastrol is a natural compound extracted from the traditional Chinese medicinal herb, Tripterygium wilfordii Hook. It has attracted interests for its potential anti-inflammatory and antitumor effects. However, the molecular mechanisms of celastrol-induced apoptosis in cancer cells remain unclear. In this study, we investigated the effects of celastrol on the human non-small-cell lung cancer (NSCLC) cell line A549 in vitro. Celastrol caused a dose- and time-dependent growth inhibition of A549 cells with an IC(50) of 2.12 μM at 48 h treatment. Celastrol induced A549 cells apoptosis as confirmed by annexin V/propidium iodide staining and DNA fragmentation. Celastrol-induced apoptosis was characterized by cleavage of caspase-9, caspase-8, caspase-3, and PARP protein, increased Fas and FasL expression, and a reduction in the mitochondrial membrane potential. Furthermore, celastrol induced the release of cytochrome c. Celastrol also up-regulated the expression of pro-apoptotic Bax, down-regulated anti-apoptotic Bcl-2, and inhibited Akt phosphorylation. These results demonstrate that celastrol can induce apoptosis of human NSCLC A549 cells through activation of both mitochondria- and FasL-mediated pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5 / analysis
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Caspase 9 / genetics
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cytochromes c / metabolism
  • DNA Fragmentation / drug effects
  • Down-Regulation
  • Fas Ligand Protein / genetics*
  • Fas Ligand Protein / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibitory Concentration 50
  • Medicine, Chinese Traditional
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Propidium / analysis
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Triterpenes / pharmacology*
  • Up-Regulation
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • fas Receptor / genetics*
  • fas Receptor / metabolism

Substances

  • Annexin A5
  • Antineoplastic Agents, Phytogenic
  • FAS protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Triterpenes
  • bcl-2-Associated X Protein
  • fas Receptor
  • Propidium
  • Cytochromes c
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • tripterine