title: 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.
authors: Basic Medical Science Education Center, Fooyin University, Kaohsiung, Taiwan.
authors: Chung-Yi
authors: CY
authors: Chen
authors: Ya-Ling
authors: YL
authors: Hsu
authors: Yin-Yi
authors: YY
authors: Chen
authors: Jen-Yu
authors: JY
authors: Hung
authors: Ming-Shyan
authors: MS
authors: Huang
authors: Po-Lin
authors: PL
authors: Kuo
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C512093:kotomolide A; D015107:4-Butyrolactone