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

Authors
 Yu Ri Kim  ;  Ju In Eom  ;  Soo Jeong Kim  ;  Hoi Kyung Jeung  ;  June-Won Cheong  ;  Jin Seok Kim  ;  Yoo Hong Min 
Citation
 JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol.335(2) : 389-400, 2010 
Journal Title
 JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 
ISSN
 0022-3565 
Issue Date
2010
MeSH
Animals ; Antineoplastic Agents, Phytogenic/pharmacology* ; Antineoplastic Agents, Phytogenic/therapeutic use ; Apoptosis/drug effects* ; Blotting, Western ; Cell Line, Tumor ; Flow Cytometry ; Glutathione/metabolism ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/enzymology* ; Leukemia, Myeloid, Acute/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred Strains ; Neoplastic Stem Cells/drug effects* ; Neoplastic Stem Cells/enzymology ; Neoplastic Stem Cells/pathology ; Peroxidase/antagonists & inhibitors ; Peroxidase/biosynthesis* ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Sesquiterpenes/pharmacology* ; Sesquiterpenes/therapeutic use ; Transfection ; Xenograft Model Antitumor Assays
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
Files in This Item:
T201003486.pdf Download
DOI
10.1124/jpet.110.169367
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Soo Jeong(김수정) ORCID logo https://orcid.org/0000-0001-8859-3573
Kim, Yu Ri(김유리) ORCID logo https://orcid.org/0000-0001-5505-0142
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Eom, Ju In(엄주인)
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/102283
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