A novel isoflavone, ME-344, targets the cytoskeleton in acute myeloid leukemia

// Danny V. Jeyaraju 1 , Rose Hurren 1 , Xiaoming Wang 1 , Neil MacLean 1 , Marcela Gronda 1 , Aisha Shamas-Din 1 , Mark D. Minden 1 , Guri Giaever 2 , Aaron D. Schimmer 1 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 2 Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada Correspondence to: Aaron D. Schimmer, email: aaron.schimmer@utoronto.ca Keywords: tubulin, leukemia, synergy, mitochondria, reactive oxygen species Received: October 19, 2015      Accepted: June 26, 2016      Published: July 06, 2016 ABSTRACT The isoflavone ME-344 is a potent anti-cancer agent with preclinical and clinical efficacy in solid tumors. Yet, the mechanism of action of ME-344 has not been fully defined and the preclinical efficacy in leukemia has not been established. Therefore, we investigated the anti-leukemic properties and mechanism of action of ME-344. In a panel of 7 leukemia cell lines, ME-344 was cytotoxic with an IC 50 in the range of 70–260 nM. In addition, ME-344 was cytotoxic to primary AML patient samples over normal hematopoietic cells. In an OCI-AML2 xenograft model, ME-344 reduced tumor growth by up to 95% of control without evidence of toxicity. Mechanistically, ME-344 increased mitochondrial ROS generation in leukemic cells. However, antioxidant treatment did not rescue cell death, suggesting that ME-344 had additional targets beyond the mitochondria. We demonstrated that ME-344 inhibited tubulin polymerization by interacting with tubulin near the colchicine-binding site. Furthermore, inhibition of tubulin polymerization was functionally important for ME-344 induced death. Finally, we showed that ME-344 synergizes with vinblastine in leukemia cells. Thus, our study demonstrates that ME-344 displays preclinical efficacy in leukemia through a mechanism at least partly related to targeting tubulin polymerization.