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Isokotomolide A, a new butanolide extracted from the leaves of Cinnamomum kotoense, arrests cell cycle progression and induces apoptosis through the induction of p53/p21 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells.

Abstract
This study is the first to investigate isokotomolide A (IKA), a butanolide compound isolated from the leaves of Cinnamomum kotoense Kanehira & Sasaki (Lauraceaee), which exhibits an anti-proliferative activity in human non-small cell lung cancer A549 cells. The results show that IKA inhibits the proliferation of A549 by blocking cell cycle progression in the G0/G1 phase and inducing apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclin D1, cyclin E, Cdk2, Cdk4, and Cdk6 in a p53-mediated manner. IKA treatment also increased p53 phosphorylation (Ser15) and decreased the interaction of p53-MDM2. IKA treatment triggered the mitochondrial apoptotic pathway, indicated by changing Bax/Bcl-2 ratios, cytochrome c release and caspase-9 activation. In addition, pre-treatment of cells with caspase-9 inhibitor inhibited IKA-induced apoptosis, indicating that caspase-9 activation was involved in A549 cells' apoptosis induced by IKA. Our study reports here for the first time that the induction of p53/p21 and the initiation of the mitochondrial apoptotic system may participate in the anti-proliferative activity of IKA in human non-small cell lung cancer cells.
AuthorsChung-Yi Chen, Ya-Ling Hsu, Yin-Yi Chen, Jen-Yu Hung, Ming-Shyan Huang, Po-Lin Kuo
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 574 Issue 2-3 Pg. 94-102 (Nov 28 2007) ISSN: 0014-2999 [Print] Netherlands
PMID17707793 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53
  • kotomolide A
  • 4-Butyrolactone
Topics
  • 4-Butyrolactone (analogs & derivatives, pharmacology)
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Apoptosis (drug effects)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
  • Humans
  • Lung Neoplasms (drug therapy, pathology)
  • Mitochondria (drug effects)
  • Tumor Suppressor Protein p53 (analysis, physiology)

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