Myeloperoxidase is a key regulator of oxidative stress-mediated apoptosis in myeloid leukemic cells

Tomonori Nakazato, Morihiko Sagawa, Kenji Yamato, Mingji Xian, Takehiro Yamamoto, Makoto Suematsu, Yasuo Ikeda, Masahiro Kizaki

Research output: Contribution to journalArticle

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Abstract

Purpose: We reported previously that reactive oxygen species (ROS) are key mediators of apoptosis induced by a polyphenol, (-)-epigallocatechin-3-gallate (EGCG), in myeloid leukemic cells. This study aimed to further examine the mechanism of ROS-mediated apoptosis induced by EGCG and its relationship to the heme enzyme myeloperoxidase (MPO). Experimental Design: We established stably transfected K562 cells expressing wild-type and mutant MPO. Then, sensitivity against EGCG and other ROS-inducing agent was examined and further investigated the detailed molecular mechanism of ROS-inducing apoptosis in MPO-positive leukemic cells. Results: EGCG rapidly induced apoptosis in MPO-positive leukemia cells. Preincubation of myeloid leukemic cells with the MPO-specific inhibitor, 4-aminobenzoic acid hydrazide, and the heme biosynthesis inhibitor, succinylacetone, resulted in inhibition of the intracellular MPO activity, ROS production, and induction of apoptosis following addition of EGCG. Overexpression of MPO sensitized EGCG-resistant K562 cells to apoptosis induced by EGCG. In contrast, an enzymatically inactive MPO mutant-expressing K562 cell could not respond to EGCG, suggesting that MPO is important for determining the sensitivity to EGCG-induced oxidative stress. Hypochlorous acid scavengers and the hydroxyl radical (·OH) scavenger inhibited EGCG-induced apoptosis in myeloid leukemic cells. The fluorescence intensity of both aminophenyl fluorescein- and hydroxyphenyl fluorescein-loaded myeloid leukemic cells significantly increased on stimulation with EGCG, indicating that EGCG generated highly toxic ROS in myeloid leukemic cells. Conclusions: These results indicated that highly toxic ROS such as ·OH generated via the hydrogen peroxide/MPO/halide system induce apoptosis and that ROS may be the direct mediators of EGCG-induced apoptosis in MPO-positive leukemic cells.

Original languageEnglish
Pages (from-to)5436-5445
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
Publication statusPublished - 2007 Sep 15

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Myeloid Cells
Peroxidase
Oxidative Stress
Apoptosis
Reactive Oxygen Species
K562 Cells
Poisons
Heme
epigallocatechin gallate
Hypochlorous Acid
Polyphenols
Hydroxyl Radical
Hydrogen Peroxide
Leukemia
Research Design
Fluorescence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Myeloperoxidase is a key regulator of oxidative stress-mediated apoptosis in myeloid leukemic cells. / Nakazato, Tomonori; Sagawa, Morihiko; Yamato, Kenji; Xian, Mingji; Yamamoto, Takehiro; Suematsu, Makoto; Ikeda, Yasuo; Kizaki, Masahiro.

In: Clinical Cancer Research, Vol. 13, No. 18, 15.09.2007, p. 5436-5445.

Research output: Contribution to journalArticle

Nakazato, T, Sagawa, M, Yamato, K, Xian, M, Yamamoto, T, Suematsu, M, Ikeda, Y & Kizaki, M 2007, 'Myeloperoxidase is a key regulator of oxidative stress-mediated apoptosis in myeloid leukemic cells', Clinical Cancer Research, vol. 13, no. 18, pp. 5436-5445. https://doi.org/10.1158/1078-0432.CCR-07-0481
Nakazato, Tomonori ; Sagawa, Morihiko ; Yamato, Kenji ; Xian, Mingji ; Yamamoto, Takehiro ; Suematsu, Makoto ; Ikeda, Yasuo ; Kizaki, Masahiro. / Myeloperoxidase is a key regulator of oxidative stress-mediated apoptosis in myeloid leukemic cells. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 18. pp. 5436-5445.
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AU - Yamato, Kenji

AU - Xian, Mingji

AU - Yamamoto, Takehiro

AU - Suematsu, Makoto

AU - Ikeda, Yasuo

AU - Kizaki, Masahiro

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