Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells

Yu Ri Kim, Ju In Eom, Soo Jeong Kim, Hoi Kyung Jeung, June Won Cheong, Jinseok Kim, Yoo Hong Min

Research output: Contribution to journalArticle

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Abstract

Given that parthenolide (PTL) is an effective antileukemic agent, identifying molecular markers that predict response to PTL is important. We evaluated the role of myeloperoxidase (MPO) in determining the sensitivity of leukemia cells to PTL-induced apoptosis. In this study, the level of PTL-induced generation of reactive oxygen species (ROS) and apoptosis was significantly higher in the MPO-high leukemia cell lines compared with the MPO-low leukemia cell lines. Pretreatment of MPO-high leukemia cells with a MPO-specific inhibitor, 4-aminobenzoic acid hydrazide, or a MPO-specific small interfering RNA (siRNA) abrogated the PTL-induced ROS generation and apoptosis, indicating that MPO plays a crucial role in PTL-induced apoptosis in leukemia cells. PTL-induced apoptosis was accompanied by down-regulation of nuclear factor-κB, Bcl-xL, Mcl-1, X-linked inhibitor of apoptosis protein, and survivin and selectively observed in primary acute myeloid leukemia (AML) cells expressing higher levels of MPO (≥50%) while sparing both AML cells with lower MPO and normal CD34-positive (CD34+) normal bone marrow cells. The extent of PTL-induced apoptosis of the CD34+CD38- cell fraction was significantly greater in the MPO-high AML cases, compared with the MPO-low AML (P < 0.01) and normal CD34+ marrow cells (P < 0.01). Nonobese diabetic/severe combined immunodeficient human leukemia mouse model also revealed that PTL preferentially targets the MPO-high AML cells. Our data suggest that MPO plays a crucial role in determining the susceptibility of leukemia cells to PTL-induced apoptosis. PTL can be considered a promising leukemic stem cell-targeted therapy for AML expressing high levels of MPO.

Original languageEnglish
Pages (from-to)389-400
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume335
Issue number2
DOIs
Publication statusPublished - 2010 Nov 1

Fingerprint

Peroxidase
Leukemia
Stem Cells
Apoptosis
Acute Myeloid Leukemia
Myeloid Cells
parthenolide
Reactive Oxygen Species
X-Linked Inhibitor of Apoptosis Protein
Cell Line
Cell- and Tissue-Based Therapy
Bone Marrow Cells
Small Interfering RNA
Down-Regulation
Bone Marrow

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Kim, Yu Ri ; Eom, Ju In ; Kim, Soo Jeong ; Jeung, Hoi Kyung ; Cheong, June Won ; Kim, Jinseok ; Min, Yoo Hong. / Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 335, No. 2. pp. 389-400.
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abstract = "Given that parthenolide (PTL) is an effective antileukemic agent, identifying molecular markers that predict response to PTL is important. We evaluated the role of myeloperoxidase (MPO) in determining the sensitivity of leukemia cells to PTL-induced apoptosis. In this study, the level of PTL-induced generation of reactive oxygen species (ROS) and apoptosis was significantly higher in the MPO-high leukemia cell lines compared with the MPO-low leukemia cell lines. Pretreatment of MPO-high leukemia cells with a MPO-specific inhibitor, 4-aminobenzoic acid hydrazide, or a MPO-specific small interfering RNA (siRNA) abrogated the PTL-induced ROS generation and apoptosis, indicating that MPO plays a crucial role in PTL-induced apoptosis in leukemia cells. PTL-induced apoptosis was accompanied by down-regulation of nuclear factor-κB, Bcl-xL, Mcl-1, X-linked inhibitor of apoptosis protein, and survivin and selectively observed in primary acute myeloid leukemia (AML) cells expressing higher levels of MPO (≥50{\%}) while sparing both AML cells with lower MPO and normal CD34-positive (CD34+) normal bone marrow cells. The extent of PTL-induced apoptosis of the CD34+CD38- cell fraction was significantly greater in the MPO-high AML cases, compared with the MPO-low AML (P < 0.01) and normal CD34+ marrow cells (P < 0.01). Nonobese diabetic/severe combined immunodeficient human leukemia mouse model also revealed that PTL preferentially targets the MPO-high AML cells. Our data suggest that MPO plays a crucial role in determining the susceptibility of leukemia cells to PTL-induced apoptosis. PTL can be considered a promising leukemic stem cell-targeted therapy for AML expressing high levels of MPO.",
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Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells. / Kim, Yu Ri; Eom, Ju In; Kim, Soo Jeong; Jeung, Hoi Kyung; Cheong, June Won; Kim, Jinseok; Min, Yoo Hong.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 335, No. 2, 01.11.2010, p. 389-400.

Research output: Contribution to journalArticle

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