title: Acetyl derivative of quercetin 3-methyl ether-induced cell death in human leukemia cells is amplified by the inhibition of ERK.
abstract: Flavonoids are polyphenolic compounds that are ubiquitously in plants and display a vast array of biological activities. Here we have studied the effect of the phenylbenzo-gamma-pyrone-derivative quercetin 3-methyl ether tetracetate (QD), obtained by acetylation of the natural product quercetin 3-methyl ether, on cell viability of human leukemia HL-60 and U937 cell lines. The results show that QD was cytotoxic and induced G2-M phase cell cycle arrest on both cell lines and it was a potent apoptotic inducer on HL-60 cells. QD-induced apoptosis is (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk, (ii) associated with cytochrome c release and (iii) triggered in Bcl-2 over-expressing U937 cells. The treatment of HL-60 and U937 cells with QD also induces the activation of the mitogen-activated protein kinases (MAPKs) pathway, including c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases (ERK) 1/2. Inhibition of c-Jun N-terminal kinase by SP600125 and of p38 mitogen-activated protein kinase by SB203580 had no influence on QD-mediated apoptosis. In contrast, inhibition of ERK1/2 with the pharmacologic inhibitors U0126 or PD98059, together with QD, resulted in an important enhancement of apoptosis. Cells are sensitized to QD-mediated apoptosis after blocking ERK1/2, which suggests that inhibition of this pathway is a valuable strategy to increase the sensitivity of human leukemia HL-60 cells toward QD.
authors.affiliation: Department of Biochemistry, University of Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Rubio
authors.forename: José
authors.initials: J
authors.lastname: Quintana
authors.forename: José L
authors.initials: JL
authors.lastname: Eiroa
authors.forename: Jorge
authors.initials: J
authors.lastname: Triana
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
mesh_terms: D000107:Acetylation; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; C459210:quercetin 3-O-methyl ether; D011794:Quercetin; D048049:Extracellular Signal-Regulated MAP Kinases