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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Xiang, W; Cheong, JK; Ang, SH; Teo, B; Xu, P; Asari, K; Sun, WT; Than, H; Bunte, RM; Virshup, DM; Chuah, C

Published Date

  • October 2015

Published In

Volume / Issue

  • 6 / 32

Start / End Page

  • 33769 - 33780

PubMed ID

  • 26378050

Pubmed Central ID

  • 26378050

Electronic International Standard Serial Number (EISSN)

  • 1949-2553

International Standard Serial Number (ISSN)

  • 1949-2553

Digital Object Identifier (DOI)

  • 10.18632/oncotarget.5615

Language

  • eng