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

Haibo Mou; Yi Zheng; Peng Zhao; Hanying Bao; Weijia Fang; Nong Xu

doi:10.1016/j.tiv.2011.03.023

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.

Authors

Haibo Mou¹, Yi Zheng, Peng Zhao, Hanying Bao, Weijia Fang, Nong Xu

Affiliation

¹ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province 310003, People's Republic of China. [email protected]

PMID: 21466843
DOI: 10.1016/j.tiv.2011.03.023

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
Pentacyclic Triterpenes
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
Pentacyclic Triterpenes
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
celastrol