title: Antiglioma action of xanthones from Gentiana kochiana: Mechanistic and structure-activity requirements.
abstract: The present study identifies xanthones gentiakochianin and gentiacaulein as the active principles responsible for the in vitro antiglioma action of ether and methanolic extracts of the plant Gentiana kochiana. Gentiakochianin and gentiacaulein induced cell cycle arrest in G(2)/M and G(0)/G(1) phases, respectively, in both C6 rat glioma and U251 human glioma cell lines. The more efficient antiproliferative action of gentiakochianin was associated with its ability to induce microtubule stabilization in a cell-free assay. Both the xanthones reduced mitochondrial membrane potential and increased the production of reactive oxygen species in glioma cells, but only the effects of gentiakochianin were pronounced enough to cause caspase activation and subsequent apoptotic cell death. The assessment of structure-activity relationship in a series of structurally related xanthones from G. kochiana and Gentianella austriaca revealed dihydroxylation at positions 7, 8 of the xanthonic nucleus as the key structural feature responsible for the ability of gentiakochianin to induce microtubule-associated G(2)/M cell block and apoptotic cell death in glioma cells.
authors.affiliation: Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Isakovic
authors.forename: Teodora
authors.initials: T
authors.lastname: Jankovic
authors.forename: Ljubica
authors.initials: L
authors.lastname: Harhaji
authors.forename: Sladjana
authors.initials: S
authors.lastname: Kostic-Rajacic
authors.forename: Zoran
authors.initials: Z
authors.lastname: Nikolic
authors.forename: Vlatka
authors.initials: V
authors.lastname: Vajs
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D030012:Gentiana / Q000737:chemistry*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D044004:Xanthones; C479001:gentiacaulein; C479000:gentiakochianin