title: Flavonoids induce apoptosis in human leukemia U937 cells through caspase- and caspase-calpain-dependent pathways.
abstract: Flavonoids are polyphenolic phytochemicals that are ubiquitous in plants and present in the common human diet. They may exert diverse beneficial effects, including antioxidant and anticarcinogenic activities. In this study we tested the apoptotic activity of 22 flavonoids and related compounds in leukemic U937 cells. Several flavones but none of the isoflavones or flavanones tested induced apoptotic cell death under these conditions, as determined by reduction in cell viability, flow cytometry, and oligonucleosomal DNA fragmentation. Structure-activity relationship showed that at least two hydroxylations in positions 3, 5, and 7 of the A ring were needed to induce apoptosis, whereas hydroxylation in 3' and/or 4' of the B ring enhanced proapoptotic activity. At lower concentrations, these compounds were also able to sensitize these cells to apoptosis induced by tumor necrosis factor-alpha. Regarding the mechanisms, galangin, luteolin, chrysin, and quercetin induced apoptosis in a way that required the activation of caspases 3 and 8, but not caspase 9. In contrast, an active role of calpains in addition to caspases was demonstrated in apoptosis induced by fisetin, apigenin, and 3,7-dihydroxyflavone. Our data show evidence of the proapoptotic properties of some flavonoids that could support their rational use as chemopreventive and therapeutic agents against carcinogenic disease.
authors.affiliation: Departamento di Bioquímica y Biología Molecular, Universidad de Navarra, Pamplona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Monasterio
authors.forename: María C
authors.initials: MC
authors.lastname: Urdaci
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pinchuk
authors.forename: Natalia
authors.initials: N
authors.lastname: López-Moratalla
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Martínez-Irujo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000187:drug effects / Q000378:metabolism*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D005419:Flavonoids; D002154:Calpain; D020169:Caspases