title: Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety.
abstract: 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.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Chemical Synthesis, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Chemical Synthesis, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.affiliation: Department of Chemical Synthesis, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Linxiang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Jing
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D037621:Artemisinins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010545:Peroxides / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D020298:U937 Cells
chemical_list: D051017:Apoptosis Regulatory Proteins; D037621:Artemisinins; C498702:PMAIP1 protein, human; D010545:Peroxides; D019253:Proto-Oncogene Proteins c-bcl-2; D013481:Superoxides; C039060:artenimol; D006861:Hydrogen Peroxide; D007501:Iron
keywords: ABT-737; acute myeloid leukemia; apoptosis; dihydroartemisinin; noxa