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

来源：

ONCOTARGET | 2016年 / 7卷 / 31期

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

页码：49777 / 49785

页数：9

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