title: Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.
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.
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Jit Kong
authors.initials: JK
authors.lastname: Cheong
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Shi Hui
authors.initials: SH
authors.lastname: Ang
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Bryan
authors.initials: B
authors.lastname: Teo
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Kartini
authors.initials: K
authors.lastname: Asari
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Wen Tian
authors.initials: WT
authors.lastname: Sun
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Hein
authors.initials: H
authors.lastname: Than
authors.affiliation: Office of Research, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.|Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Charles
authors.initials: C
authors.lastname: Chuah
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis; D001752:Blast Crisis / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000069439:Dasatinib / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011774:Pyrvinium Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D034622:RNA Interference; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D011774:Pyrvinium Compounds; D051176:beta Catenin; C024631:pyrvinium; D000255:Adenosine Triphosphate; D047389:Casein Kinase I; D000069439:Dasatinib
keywords: chronic myeloid leukemia; mitochondrial respiration; pyrvinium