Article ; Online: Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.
2015 Volume 6, Issue 32, Page(s) 33769–33780
Abstract: ... in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less ... anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing ... to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium ...
| 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/β-catenin signalling pathway via activation of casein kinase 1α , 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. |
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| MeSH term(s) | Adenosine Triphosphate/chemistry ; Animals ; Antigens, CD34/metabolism ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Apoptosis ; Blast Crisis/metabolism ; Casein Kinase I/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Dasatinib/administration & dosage ; Dasatinib/therapeutic use ; Humans ; Inhibitory Concentration 50 ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Mice ; Mice, SCID ; Mitochondria/metabolism ; Neoplasm Transplantation ; Phosphorylation ; Pyrvinium Compounds/administration & dosage ; Pyrvinium Compounds/therapeutic use ; RNA Interference ; beta Catenin/metabolism |
| Chemical Substances | Antigens, CD34 ; Pyrvinium Compounds ; beta Catenin ; pyrvinium (6B9991FLU3) ; Adenosine Triphosphate (8L70Q75FXE) ; Casein Kinase I (EC 2.7.11.1) ; Dasatinib (RBZ1571X5H) |
| Language | English |
| Publishing date | 2015-10-20 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2560162-3 |
| ISSN | 1949-2553 ; 1949-2553 |
| ISSN (online) | 1949-2553 |
| ISSN | 1949-2553 |
| DOI | 10.18632/oncotarget.5615 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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