title: Furano-1,2-naphthoquinone inhibits EGFR signaling associated with G2/M cell cycle arrest and apoptosis in A549 cells.
abstract: Furano-1,2-naphthoquinone (FNQ), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti-carcinogenic effect. FNQ exerted anti-proliferative activity with the G(2)/M cell cycle arrest and apoptosis in A549 cells. FNQ-induced G(2)/M arrest was correlated with a marked decrease in the expression levels of cyclin A and cyclin B, and their activating partner cyclin-dependent kinases (Cdk) 1 and 2 with concomitant induction of p53, p21, and p27. FNQ-induced apoptosis was accompanied with Bax up-regulation and the down-regulation of Bcl-2, X-linked inhibitor of apoptosis (XIAP), and survivin, resulting in cytochrome c release and sequential activation of caspase-9 and caspase-3. Western blot analysis revealed that FNQ suppressed EGFR phosphorylation and JAK2, STAT3, and STAT5 activation, but increased in activation of p38 MAPK and c-Jun NH2-terminal kinase (JNK) stress signal. The combined treatment of FNQ with AG1478 (a specific EGFR inhibitor) significantly enhanced the G(2)/M arrest and apoptosis, and also led to up-regulation in Bax, p53, p21, p27, release of mitochondrial cytochrome c, and down-regulation of Bcl-2, XIAP, survivin, cyclin A, cyclin B, Cdk1, and Cdk2 in A549 cells. These findings suggest that FNQ-mediated cytotoxicity of A549 cell related with the G(2)/M cell cycle arrest and apoptosis via inactivation of EGFR-mediated signaling pathway.
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: J C
authors.initials: JC
authors.lastname: Su
authors.forename: K L
authors.initials: KL
authors.lastname: Lin
authors.forename: C M
authors.initials: CM
authors.lastname: Chien
authors.forename: C H
authors.initials: CH
authors.lastname: Tseng
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: L S
authors.initials: LS
authors.lastname: Chang
authors.forename: S R
authors.initials: SR
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000502:physiology*; D005663:Furans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000378:metabolism; D008175:Lung Neoplasms; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009285:Naphthoquinones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D005663:Furans; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C556022:furano-1,2-naphthoquinone; D066246:ErbB Receptors; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases