title: Multitarget effects of quercetin in leukemia.
abstract: This study proposes to investigate quercetin antitumor efficacy in vitro and in vivo, using the P39 cell line as a model. The experimental design comprised leukemic cells or xenografts of P39 cells, treated in vitro or in vivo, respectively, with quercetin; apoptosis, cell-cycle and autophagy activation were then evaluated. Quercetin caused pronounced apoptosis in P39 leukemia cells, followed by Bcl-2, Bcl-xL, Mcl-1 downregulation, Bax upregulation, and mitochondrial translocation, triggering cytochrome c release and caspases activation. Quercetin also induced the expression of FasL protein. Furthermore, our results demonstrated an antioxidant activity of quercetin. Quercetin treatment resulted in an increased cell arrest in G1 phase of the cell cycle, with pronounced decrease in CDK2, CDK6, cyclin D, cyclin E, and cyclin A proteins, decreased Rb phosphorylation and increased p21 and p27 expression. Quercetin induced autophagosome formation in the P39 cell line. Autophagy inhibition induced by quercetin with chloroquine triggered apoptosis but did not alter quercetin modulation in the G1 phase. P39 cell treatment with a combination of quercetin and selective inhibitors of ERK1/2 and/or JNK (PD184352 or SP600125, respectively), significantly decreased cells in G1 phase, this treatment, however, did not change the apoptotic cell number. Furthermore, in vivo administration of quercetin significantly reduced tumor volume in P39 xenografts and confirmed in vitro results regarding apoptosis, autophagy, and cell-cycle arrest. The antitumor activity of quercetin both in vitro and in vivo revealed in this study, point to quercetin as an attractive antitumor agent for hematologic malignancies.
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Maso
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Andrana Karla
authors.initials: AK
authors.lastname: Calgarotto
authors.affiliation: Onco-Hematological Child Research Center, Faculty of Medical Sciences, University of Campinas-Unicamp, Campinas, São Paulo, Brazil.
authors.forename: Gilberto Carlos
authors.initials: GC
authors.lastname: Franchi
authors.affiliation: Onco-Hematological Child Research Center, Faculty of Medical Sciences, University of Campinas-Unicamp, Campinas, São Paulo, Brazil.
authors.forename: Alexandre Eduardo
authors.initials: AE
authors.lastname: Nowill
authors.affiliation: Department of Pathology, Faculty of Medical Sciences, Laboratory of Investigative and Molecular Pathology, CIPED, FCM-Unicamp, Campinas, Brazil.
authors.forename: Paulo Latuf
authors.initials: PL
authors.lastname: Filho
authors.affiliation: Department of Pathology, Faculty of Medical Sciences, Laboratory of Investigative and Molecular Pathology, CIPED, FCM-Unicamp, Campinas, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. sara@unicamp.br.
authors.forename: Sara Teresinha Olalla
authors.initials: ST
authors.lastname: Saad
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D014408:Biomarkers, Tumor; D017382:Reactive Oxygen Species; D011794:Quercetin