title: Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft.
abstract: Quercetin is a plant-derived bioflavonoid that was recently shown to have multiple anticancer activities in various solid tumors. Here, novel molecular mechanisms through which quercetin exerts its anticancer effects in acute myeloid leukemia (AML) cells were investigated. Results from Western blot and flow cytometric assays revealed that quercetin significantly induced caspase-8, caspase-9, and caspase-3 activation, poly ADP-ribose polymerase (PARP) cleavage, and mitochondrial membrane depolarization in HL-60 AML cells. The induction of PARP cleavage by quercetin was also observed in other AML cell lines: THP-1, MV4-11, and U937. Moreover, treatment of HL-60 cells with quercetin induced sustained activation of extracellular signal-regulated kinase (ERK), and inhibition of ERK by an ERK inhibitor significantly abolished quercetin-induced cell apoptosis. MitoSOX red and 2',7'-dichlorofluorescin fluorescence, respectively, showed that mitochondrial superoxide and intracellular peroxide levels were higher in quercetin-treated HL-60 cells compared with the control group. Moreover, both N-acetylcysteine and the superoxide dismutase mimetic, MnTBAP, reversed quercetin-induced intracellular reactive oxygen species production, ERK activation, and subsequent cell death. The in vivo xenograft mice experiments revealed that quercetin significantly reduced tumor growth through inducing intratumoral oxidative stress while activating the ERK pathway and subsequent cell apoptosis in mice with HL-60 tumor xenografts. In conclusions, our results indicated that quercetin induced cell death of HL-60 cells in vitro and in vivo through induction of intracellular oxidative stress following activation of an ERK-mediated apoptosis pathway.
authors.affiliation: Department of Urology, Wan Fang Hospital, Taipei Medical University, 111 Hsing Long Road, Section 3, Taipei, 116, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Junn-Liang
authors.initials: JL
authors.lastname: Chang
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.forename: Tsui-Hwa
authors.initials: TH
authors.lastname: Tseng
authors.forename: Chao-Wen
authors.initials: CW
authors.lastname: Cheng
authors.forename: Jyh-Ming
authors.initials: JM
authors.lastname: Chow
authors.forename: Ke-Hsun
authors.initials: KH
authors.lastname: Lin
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Lin
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Liu
authors.forename: Liang-Ming
authors.initials: LM
authors.lastname: Lee
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008819:Mice, Nude; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D011794:Quercetin; D048049:Extracellular Signal-Regulated MAP Kinases