title: Antiproliferative activity and apoptosis induction by 3',4'-dibenzyloxyflavonol on human leukemia cells.
abstract: In this study, we investigated the effects of synthetic 3',4'-dibenzyloxyflavonol on viabilities of eight human tumor cells. It was cytotoxic against leukemia cells (HL-60, U-937, MOLT-3, K-562, NALM-6, Raji), with significant effects against P-glycoprotein-overexpressing K-562/ADR and Bcl-2-overexpressing U-937/Bcl-2 cells, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. The IC50value for the leukemia HL-60 cells was 0.8 ± 0.1 μM. This indicates a 60-fold greater toxicity than the naturally occurring flavonol quercetin. Synthetic 3',4'-dibenzyloxyflavonol induced S phase cell cycle arrest and was a potent apoptotic inducer in human leukemia cells. Cell death was (i) mediated by the activation and the cleavage of initiator and executioner caspases; (ii) prevented by the pan-caspase inhibitor z-VAD-fmk; (iii) associated with the release of cytochrome c and with the phosphorylation of members of the mitogen activated protein kinases including p38MAPK, JNK/SAPK and ERK, and (iv) independent of the generation of reactive oxygen species. The synthetic 3',4'-dibenzyloxyflavonol is a potent cytotoxic compound against several human leukemia cells and might be useful in the development of new strategies in the fight against cancer.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Unidad Asociada al Consejo Superior de Investigaciones Científicas (CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de las Palmas de Gran Canaria, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Said
authors.affiliation: Instituto de Productos Naturales y Agrobiología, CSIC, La Laguna, Tenerife, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Brouard
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Unidad Asociada al Consejo Superior de Investigaciones Científicas (CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de las Palmas de Gran Canaria, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Quintana
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Unidad Asociada al Consejo Superior de Investigaciones Científicas (CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de las Palmas de Gran Canaria, Spain. Electronic address: francisco.estevez@ulpgc.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D044948:Flavonols / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C000617642:3',4'-dibenzyloxyflavonol; D000970:Antineoplastic Agents; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D044948:Flavonols; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: Apoptosis; Caspases; Cell cycle; Cytotoxicity; Flavonoids