Tao Zhen,
Chuan-Feng Wu,
Ping Liu,
Hai-Yan Wu,
Guang-Biao Zhou,
Ying Lu,
Jian-Xiang Liu,
Yang Liang,
Keqin Kathy Li,
Yue-Ying Wang,
Yin-Yin Xie,
Miao-Miao He, Huang-Ming Cao,
Wei-Na Zhang,
Li-Min Chen,
Kevin Petrie,
Sai-Juan Chen,
Zhu Chen
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ABSTRACT: Nearly 60% of acute myeloid leukemia (AML) patients with the t(8;21)(q22;q22) translocation fail to achieve long-term disease-free survival. Our previous studies demonstrated that oridonin selectively induces apoptosis of t(8;21) leukemia cells and causes cleavage of AML1-ETO oncoprotein resulting from t(8;21), but the underlying mechanisms remain unclear. We show that oridonin interacted with glutathione and thioredoxin/thioredoxin reductase to increase intracellular reactive oxygen species, which in turn activated caspase-3 in t(8;21) cells. Moreover, oridonin bound AML1-ETO, directing the enzymatic cleavage at aspartic acid 188 via caspase-3 to generate a truncated AML1-ETO (ΔAML1-ETO) and preventing the protein from further proteolysis. ΔAML1-ETO interacted with AML1-ETO and interfered with the trans-regulatory functions of remaining AML1-ETO oncoprotein, thus acting as a tumor suppressor that mediates the anti-leukemia effect of oridonin. Furthermore, oridonin inhibited the activity of c-Kit(+) leukemia-initiating cells. Therefore, oridonin is a potential lead compound for molecular target-based therapy of leukemia.
Science translational medicine 03/2012; 4(127):127ra38. · 7.80 Impact Factor
