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Molecular mechanisms of echinocystic acid-induced apoptosis in HepG2 cells.

Abstract
Echinocystic acid (EA), a natural triterpone enriched in various herbs, has been showed to have cytotoxic activity in some cancer cells, and is used for medicinal purpose in many Asian countries. In the present study, we found that EA could induce apoptosis in human HepG2 cells, as characterized by DNA fragmentation, activation of caspase-3, -8, and -9, and PARP cleavage. The efficacious induction of apoptosis was observed at 45 microM for 24 h. Molecular data showed that EA induced the truncation of Bid protein and reduction of Bcl-2 protein. EA also caused the loss of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release from mitochondria to cytosol. Moreover, EA could activate c-Jun NH(2)-terminal kinase (JNK) and p38 kinase, and JNK-specific inhibitor SP600125 and p38 kinase-specific inhibitor SB200235 could block serial molecular events of EA-induced apoptosis such as Bid truncation, Bcl-2 reduction, cytochrome c release, caspase activation, and DNA fragmentation in HepG2 cells. These findings indicate that JNK- and p38 kinase-mediated mitochondrial pathways might be involved in EA-induced apoptosis and enhance our understanding of the anticancer function of EA in herbal medicine.
AuthorsXuhui Tong, Shigang Lin, Makoto Fujii, De-Xing Hou
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 321 Issue 3 Pg. 539-46 (Aug 27 2004) ISSN: 0006-291X [Print] United States
PMID15358141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Oleanolic Acid
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Caspases
  • echinocystic acid
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein
  • Carcinoma, Hepatocellular (drug therapy, physiopathology)
  • Carrier Proteins (metabolism)
  • Caspases (metabolism)
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • DNA Fragmentation
  • Enzyme Activation
  • Enzyme Inhibitors (metabolism)
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Liver Neoplasms (drug therapy, physiopathology)
  • Mitochondria (metabolism)
  • Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • Oleanolic Acid (analogs & derivatives, pharmacology, therapeutic use)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Signal Transduction (physiology)
  • p38 Mitogen-Activated Protein Kinases

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