title: Polyphenol-Rich Fraction from Larrea divaricata and its Main Flavonoid Quercetin-3-Methyl Ether Induce Apoptosis in Lymphoma Cells Through Nitrosative Stress.
abstract: Larrea divaricata is a plant with antiproliferative principles. We have previously identified the flavonoid quercetin-3-methyl ether (Q-3-ME) in an ethyl acetate fraction (EA). Both the extract and Q-3-ME were found to be effective against the EL-4 T lymphoma cell line. However, the mechanism underlying the inhibition of tumor cell proliferation remains to be elucidated. In this work, we analyzed the role of nitric oxide (NO) in the induction of apoptosis mediated by Q-3-ME and EA. Both treatments were able to induce apoptosis in a concentration-dependent and time-dependent manner. The western blot analysis revealed a sequential activation of caspases-9 and 3, followed by poly-(ADP-ribose)-polymerase cleavage. EA and Q-3-ME lowered the mitochondrial membrane potential, showing the activation of the intrinsic pathway of apoptosis. Q-3-ME and EA increased NO production and inducible NO synthase expression in tumor cells. The involvement of NO in cell death was confirmed by the nitric oxide synthases inhibitor L-NAME. In addition, EA and Q-3-ME induced a cell cycle arrest in G0/G1 phase. These drugs did not affect normal cell viability. This data suggested that EA and Q-3-ME induce an increase in NO production that would lead to the cell cycle arrest and the activation of the intrinsic pathway of apoptosis. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Instituto de Química y Metabolismo del Fármaco - IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 piso 2, 1113, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Renzo
authors.initials: R
authors.lastname: Martino
authors.affiliation: Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Av. A. Moreau de Justo 1600, piso 3, 1107AFF, Buenos Aires, Argentina.
authors.forename: María Laura Barreiro
authors.initials: ML
authors.lastname: Arcos
authors.affiliation: Instituto de Química y Metabolismo del Fármaco - IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 piso 2, 1113, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Rosario
authors.initials: R
authors.lastname: Alonso
authors.affiliation: Instituto de Química y Metabolismo del Fármaco - IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 piso 2, 1113, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sülsen
authors.affiliation: Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Av. A. Moreau de Justo 1600, piso 3, 1107AFF, Buenos Aires, Argentina.
authors.forename: Graciela
authors.initials: G
authors.lastname: Cremaschi
authors.affiliation: Instituto de Química y Metabolismo del Fármaco - IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 piso 2, 1113, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Anesini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D032442:Larrea / Q000737:chemistry*; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols / Q000494:pharmacology*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010936:Plant Extracts; D059808:Polyphenols; C459210:quercetin 3-O-methyl ether; D009569:Nitric Oxide; D011794:Quercetin
keywords: Larrea divaricata; T lymphoma cells; apoptosis; ethyl acetate fraction; nitric oxide; quercetin-3-methyl ether