Induction of leukemia cell apoptosis by cheliensisin A involves down-regulation of Bcl-2 expression.

To investigate the apoptosis-inducing effect of cheliensisin A (GC-51), a novel styryl-lactone isolated from Goniothalamus cheliensis, on human promyelocytic leukemia HL-60 cells and the mechanism of action involved.
Apoptotic cell death was determined by morphological examination and DNA agarose gel electrophoresis. The activity of caspase-3 was assessed using Western blotting and the expression of Bcl-2 and Bax genes was analyzed using the reverse transcription-polymerase chain reaction (RT-PCR) method.
GC-51 significantly inhibited the proliferation of HL-60 cells with an IC50 of 2.4+/-0.2 micromol/L and effectively induced apoptosis in HL-60 cells. Exposure of HL-60 cells to 10 micromol/L GC-51 for 8 h resulted in approximately 53% of the cells undergoing apoptosis. Caspase-3 was activated in GC-51-treated cells, which was manifested by the appearance of the 17 kDa active form of caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP). Meanwhile, GC-51 markedly reduced the expression of the anti-apoptotic gene Bcl-2 and increased the expression of the pro-apoptotic gene Bax. The apoptosis-inducing effect of GC-51 was cAMP-dependent protein kinase (PKA) dependent because PKA, but not the protein kinase C, specific inhibitor H-89, blocked the induction of apoptosis by GC-51 in HL-60 cells.
The results demonstrate that GC-51 effectively induces apoptosis in HL-60 cells and that this effect is PKA-dependent and involves the downregulation of Bcl-2 expression and the activation of caspase-3.
AuthorsLi Zhong, Chao-ming Li, Xiao-jiang Hao, Li-guang Lou
JournalActa pharmacologica Sinica (Acta Pharmacol Sin) Vol. 26 Issue 5 Pg. 623-8 (May 2005) ISSN: 1671-4083 [Print] China
PMID15842784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • BAX protein, human
  • Epoxy Compounds
  • Isoquinolines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrones
  • Sulfonamides
  • bcl-2-Associated X Protein
  • cheliensisin A
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Cyclic AMP-Dependent Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Annonaceae (chemistry)
  • Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
  • Apoptosis (drug effects)
  • Caspase 3
  • Caspases (metabolism)
  • Cell Proliferation (drug effects)
  • Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors)
  • Epoxy Compounds (chemistry, isolation & purification, pharmacology)
  • Gene Expression Regulation, Neoplastic
  • HL-60 Cells
  • Humans
  • Isoquinolines (pharmacology)
  • Plants, Medicinal (chemistry)
  • Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
  • Pyrones (chemistry, isolation & purification, pharmacology)
  • Sulfonamides (pharmacology)
  • bcl-2-Associated X Protein

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