Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.5615
Title: Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration
Authors: Xiang W.
Cheong J.K. 
Ang S.H. 
Teo B.
Xu P. 
Asari K.
Sun W.T. 
Than H.
Bunte R.M. 
Virshup D.M. 
Chuah C. 
Keywords: beta catenin
casein kinase Ialpha
CD34 antigen
dasatinib
pyrvinium embonate
Wnt protein
adenosine triphosphate
antineoplastic agent
beta catenin
casein kinase I
CD34 antigen
dasatinib
pyrvinium embonate
animal experiment
animal model
animal tissue
antineoplastic activity
apoptosis
Article
cancer inhibition
cell renewal
chronic myeloid leukemia
colony formation
controlled study
human
human cell
mitochondrial respiration
mouse
nonhuman
protein protein interaction
signal transduction
stem cell
tumor xenograft
umbilical cord blood
animal
blast cell crisis
cancer transplantation
cell proliferation
chemistry
IC50
K-562 cell line
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
metabolism
mitochondrion
phosphorylation
RNA interference
SCID mouse
tumor cell line
Adenosine Triphosphate
Animals
Antigens, CD34
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
beta Catenin
Blast Crisis
Casein Kinase I
Cell Line, Tumor
Cell Proliferation
Dasatinib
Humans
Inhibitory Concentration 50
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Mice
Mice, SCID
Mitochondria
Neoplasm Transplantation
Phosphorylation
Pyrvinium Compounds
RNA Interference
Issue Date: 2015
Citation: Xiang W., Cheong J.K., Ang S.H., Teo B., Xu P., Asari K., Sun W.T., Than H., Bunte R.M., Virshup D.M., Chuah C. (2015). Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration. Oncotarget 6 (32) : 33769-33780. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.5615
Abstract: The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells from TKI-resistant BP-CML patients, while cord blood CD34+ are largely unaffected. The effects of pyrvinium are further enhanced upon combination with dasatinib, a second generation BCR-ABL1 TKI. In a CML xenograft model pyrvinium significantly inhibits tumor growth as a single agent, with complete inhibition in combination with dasatinib. While pyrvinium has been shown to inhibit the Wnt/ß-catenin signalling pathway via activation of casein kinase 1a, we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium is a useful addition to the treatment armamentarium for BP-CML and that targeting mitochondrial respiration may be a potential therapeutic strategy in aggressive leukemia.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174134
ISSN: 19492553
DOI: 10.18632/oncotarget.5615
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