title: A novel isoflavone, ME-344, targets the cytoskeleton in acute myeloid leukemia.
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.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Danny V
authors.initials: DV
authors.lastname: Jeyaraju
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: MacLean
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Aisha
authors.initials: A
authors.lastname: Shamas-Din
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D049109:Cell Proliferation; D002470:Cell Survival; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007529:Isoflavones / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D007529:Isoflavones; D017382:Reactive Oxygen Species; D014404:Tubulin; C000597890:ME-344
keywords: leukemia; mitochondria; reactive oxygen species; synergy; tubulin