Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft

Wei-Jiunn Lee, Michael Hsiao, Junn Liang Chang, Shun Fa Yang, Tsui H. Tseng, Chao-Wen Cheng, Jyh-Ming Chow, Ke Hsun Lin, Yung Wei Lin, Chung Chi Liu, Liang-Ming Lee, Ming-Hsien Chien

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69 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1103-1117
Number of pages15
JournalArchives of Toxicology
Issue number7
Publication statusPublished - Jul 15 2015


  • Acute myeloid leukemia
  • Apoptosis
  • Extracellular signal-regulated kinase
  • Quercetin
  • Reactive oxygen species

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis


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