me-344 and Leukemia--Myeloid--Acute

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.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Binding Sites; Cell Proliferation; Cell Survival; Cytoskeleton; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Inhibitory Concentration 50; Isoflavones; Leukemia, Myeloid, Acute; Male; Mice; Mice, SCID; Microtubules; Mitochondria; Neoplasm Transplantation; Protein Binding; Reactive Oxygen Species; Tubulin