Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells.
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.
Kim
Yu Ri
YR
Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea. minbrmmd@yuhs.ac
Eom
Ju In
JI
Kim
Soo Jeong
SJ
Jeung
Hoi Kyung
HK
Cheong
June-Won
JW
Kim
Jin Seok
JS
Min
Yoo Hong
YH
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C002669:parthenolide; D009195:Peroxidase; D005978:Glutathione