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Oncotarget. 2016 Aug 2;7(31):49777-49785. doi: 10.18632/oncotarget.10446.

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

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
2
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

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 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.

KEYWORDS:

leukemia; mitochondria; reactive oxygen species; synergy; tubulin

PMID:
27391350
PMCID:
PMC5226547
DOI:
10.18632/oncotarget.10446
[Indexed for MEDLINE]
Free PMC Article

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