Work

Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration

Year: 2015

Type: article

Abstract: // Wei Xiang 1,* , Jit Kong Cheong 2,* , Shi Hui Ang 2 , Bryan Teo 1 , Peng Xu 2 , Kartini Asari 1 , Wen Tian Sun 2 , Hein Than 1 , Ralph M. Bunte 3 , David M. Virshup 2,4 and Charles Chuah 1,2 1 Department of Haematology, Singapore General Hospital, Singapore 2 Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 3 Office of Research, Duke-NUS Graduate Medical School, Singapore 4 Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA * These authors have contributed equally to this work Correspondence to: Charles Chuah, email: // Keywords : chronic myeloid leukemia, pyrvinium, mitochondrial respiration Received : August 21, 2015 Accepted : August 27, 2015 Published : September 10, 2015 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.5615