Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety
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Xuan Zhao1, Hang Zhong2, Rui Wang3, Dan Liu2, Samuel Waxman3, Linxiang Zhao2 and Yongkui Jing3
1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
2 Department of Chemical Synthesis, Shenyang Pharmaceutical University, Shenyang, China
3 Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Yongkui Jing, email:
Linxiang Zhao, email:
Keywords: Dihydroartemisinin, Noxa, Apoptosis, ABT-737, Acute myeloid leukemia
Received: October 06, 2014 Accepted: January 04, 2015 Published: January 21, 2015
Anti-apoptotic protein Mcl-1 plays an important role in protecting cell from death in acute myeloid leukemia (AML). The apoptosis blocking activity of Mcl-1 is inhibited by BH3-only protein Noxa. We found that dihydroartemisinin (DHA) and its derivative X-11 are potent apoptosis inducers in AML cells and act through a Noxa-mediate pathway; X-11 is four-fold more active than DHA. DHA and X-11-induced apoptosis is associated with induction of Noxa; apoptosis is blocked by silencing Noxa. DHA and X-11 induce Noxa expression by upregulating the transcription factor FOXO3a in a reactive oxygen species-mediated pathway. Interfering with the integrity of the endoperoxide moiety of DHA and X-11, as well as chelating intracellular iron with deferoxamine, diminish apoptosis and Noxa induction. AML cells expressing Bcl-xL, or with overexpression of Bcl-2, have decreased sensitivity to DHA and X-11-induced apoptosis which could be overcome by addition of Bcl-2/Bcl-xL inhibitor ABT-737. DHA and X-11 represent a new group of AML cells-apoptosis inducing compounds which work through Noxa up-regulation utilizing the specific endoperoxide moiety and intracellular iron.
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