A novel isoflavone, ME-344, targets the cytoskeleton in acute myeloid leukemia
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Danny V. Jeyaraju1, Rose Hurren1, Xiaoming Wang1, Neil MacLean1, Marcela Gronda1, Aisha Shamas-Din1, Mark D. Minden1, Guri Giaever2, Aaron D. Schimmer1
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
2Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
Aaron D. Schimmer, email: email@example.com
Keywords: tubulin, leukemia, synergy, mitochondria, reactive oxygen species
Received: October 19, 2015 Accepted: June 26, 2016 Published: July 06, 2016
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 IC50 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.
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