title: Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines.
abstract: The lignan arctigenin (ARG) from the herb Arctium lappa L. possesses anti-cancer activity, however the mechanism of action of ARG has been found to vary among tissues and types of cancer cells. The current study aims to gain insight into the ARG mediated mechanism of action involved in inhibiting proliferation and inducing apoptosis in lung adenocarcinoma cells. This study also delineates the cancer cell specificity of ARG by comparison with its effects on various normal cell lines. ARG selectively arrested the proliferation of cancer cells at the G0/G1 phase through the down-regulation of NPAT protein expression. This down-regulation occurred via the suppression of either cyclin E/CDK2 or cyclin H/CDK7, while apoptosis was induced through the modulation of the Akt-1-related signaling pathway. Furthermore, a GSH synthase inhibitor specifically enhanced the cytotoxicity of ARG against cancer cells, suggesting that the intracellular GSH content was another factor influencing the susceptibility of cancer cells to ARG. These findings suggest that specific cytotoxicity of ARG against lung cancer cells was explained by its selective modulation of the expression of NPAT, which is involved in histone biosynthesis. The cytotoxicity of ARG appeared to be dependent on the intracellular GSH level.
authors.affiliation: United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-0065, Japan; Center of Molecular Biosciences, Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan; Department of Animal and Agricultural Sciences, Diponegoro University, Central Java, Indonesia.
authors.forename: Siti
authors.initials: S
authors.lastname: Susanti
authors.forename: Hironori
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Masashi
authors.initials: M
authors.lastname: Inafuku
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taira
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Oku
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D031170:Arctium / Q000737:chemistry*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D016213:Cyclins; D005663:Furans; D017705:Lignans; C101693:NPAT protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010936:Plant Extracts; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D005978:Glutathione; C071942:arctigenin
keywords: ARG; Arctigenin (ARG); CDK2; CDK7; Cytotoxicity; G(0)/G(1); GSH; Gap 0/Gap 1; Mechanism; NPAT; Specific; akt-1; alpha serine/threonine-protein kinase; arctigenin; cyclin-dependent kinase 2; cyclin-dependent kinase 7; glutathione; nuclear protein of the ataxia telangiectasia locus