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

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1103-1117
Number of pages15
JournalArchives of Toxicology
Volume89
Issue number7
DOIs
Publication statusPublished - Jul 15 2015

Fingerprint

HL-60 Cells
Quercetin
Extracellular Signal-Regulated MAP Kinases
Heterografts
Reactive Oxygen Species
Leukemia
Chemical activation
Apoptosis
Myeloid Cells
Acute Myeloid Leukemia
Tumors
Oxidative stress
Poly(ADP-ribose) Polymerases
Cell death
Oxidative Stress
Cell Death
Neoplasms
Caspase 9
Caspase 8
Peroxides

Keywords

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

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft. / Lee, Wei-Jiunn; Hsiao, Michael; Chang, Junn Liang; Yang, Shun Fa; Tseng, Tsui H.; Cheng, Chao-Wen; Chow, Jyh-Ming; Lin, Ke Hsun; Lin, Yung Wei; Liu, Chung Chi; Lee, Liang-Ming; Chien, Ming-Hsien.

In: Archives of Toxicology, Vol. 89, No. 7, 15.07.2015, p. 1103-1117.

Research output: Contribution to journalArticle

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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.",
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AU - Lee, Wei-Jiunn

AU - Hsiao, Michael

AU - Chang, Junn Liang

AU - Yang, Shun Fa

AU - Tseng, Tsui H.

AU - Cheng, Chao-Wen

AU - Chow, Jyh-Ming

AU - Lin, Ke Hsun

AU - Lin, Yung Wei

AU - Liu, Chung Chi

AU - Lee, Liang-Ming

AU - Chien, Ming-Hsien

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AB - 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.

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