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

被引:18
作者
Jeyaraju, Danny V. [1 ]
Hurren, Rose [1 ]
Wang, Xiaoming [1 ]
MacLean, Neil [1 ]
Gronda, Marcela [1 ]
Shamas-Din, Aisha [1 ]
Minden, Mark D. [1 ]
Giaever, Guri [2 ]
Schimmer, Aaron D. [1 ]
机构
[1] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada
[2] Univ British Columbia, Dept Pharmaceut Sci, Vancouver, BC, Canada
关键词
tubulin; leukemia; synergy; mitochondria; reactive oxygen species; INDEPENDENT CELL-DEATH; MITOCHONDRIAL GLUTATHIONE; CANCER; PHENOXODIOL; GENISTEIN;
D O I
10.18632/oncotarget.10446
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:49777 / 49785
页数:9
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