title: Gardenin B-induced cell death in human leukemia cells involves multiple caspases but is independent of the generation of reactive oxygen species.
abstract: Flavonoids have attracted great interest due to their possible anticancer activities. Here we investigated the antiproliferative activity of the flavonoids isolated from Baccharis scandens against human leukemia cell lines and found that the methoxyflavonoid gardenin B was the most cytotoxic compound against HL-60 and U-937 cells, showing IC50 values between 1.6 and 3.0 μM, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. These effects on viability were accompanied by the concentration- and time-dependent appearance of apoptosis as evidenced by DNA fragmentation, formation of apoptotic bodies and a sub-G1 ratio increase. Comparative studies with the best-studied bioflavonoid quercetin indicate that gardenin B is a more cytotoxic and more apoptotic inducer than quercetin. Cell death induced by gardenin B was associated with: (i) a significant induction of caspase-2, -3, -8 and -9 activities; (ii) cleavage of the initiator caspases (caspase-2, -8 and -9), of the executioner caspase-3, and of poly(ADP-ribose) polymerase; and (iii) a concentration-dependent reactive oxygen species generation. In conclusion, apoptosis induced by gardenin B is associated with activation of both the extrinsic and the intrinsic apoptotic pathways of cell death and occurs through a mechanism that is independent of the generation of reactive oxygen species.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cabrera
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Saavedra
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Spain.
authors.forename: Henoc
authors.initials: H
authors.lastname: Del Rosario
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Perdomo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Loro
authors.affiliation: Área de Química Orgánica, INTEQUI-CONICET, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, 5700 San Luis, Argentina.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Cifuente
authors.affiliation: Área de Química Orgánica, INTEQUI-CONICET, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, 5700 San Luis, Argentina.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Tonn
authors.affiliation: Instituto Universitario de Bio-Orgánica "Antonio González", Departamento de Química Orgánica, Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain.
authors.forename: Celina
authors.initials: C
authors.lastname: García
authors.affiliation: Departamento de Bioquímica y Biología Molecular, 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, 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: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D031175:Baccharis / Q000737:chemistry; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047309:Flavones; D017382:Reactive Oxygen Species; C000591222:gardenin B; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases
keywords: Apoptosis; Baccharis scandens; Caspases; Cytotoxicity; Flavonoids