کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8294295 | 1536751 | 2018 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
Mitochondria has been a promising target in blood cancer given their unique dependencies on mitochondrial functions compared to normal hematopoietic cells. In line with this concept, we show that an anthelminthic drug ivermectin selectively kills chronic myeloid leukemia (CML) cells via inducing mitochondrial dysfunctions and oxidative stress. Ivermectin is significantly more effective in inducing caspase-dependent apoptosis in CML cell line K562 and primary CML CD34 than normal bone marrow (NBM) CD34â¯cells. Ivermectin also augments in vitro and in vivo efficacy of standard CML tyrosine kinase inhibitors. Mechanistically, ivermectin inhibits respiratory complex I activity and suppresses mitochondrial respiration in K562 and CML CD34â¯cells. Interestingly, we demonstrate that mitochondrial respiration are lower in NBM CD34 compared to malignant CD34â¯cells. In addition, ivermectin also induces mitochondrial dysfunctions in NBM CD34â¯cells in a similar manner as in CML CD34â¯cells whereas NBM CD34â¯cells are significantly less sensitive to ivermectin than CML CD34â¯cells. These suggest that NBM CD34â¯cells are more tolerable to mitochondrial dysfunctions than CML CD34â¯cells. Consistently, ivermectin induces higher levels of oxidative stress and damage in CML than normal counterparts. Antioxidant NAC rescues ivermectin's effects, confirming oxidative stress as the mechanism of its action in CML. Our work provides the fundamental evidence to repurpose ivermectin for CML treatment. Our work also highlights the therapeutic value of targeting mitochondria respiration in CML.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 497, Issue 1, 26 February 2018, Pages 241-247
Journal: Biochemical and Biophysical Research Communications - Volume 497, Issue 1, 26 February 2018, Pages 241-247
نویسندگان
Jiaqiao Wang, Yanhua Xu, Huihui Wan, June Hu,