Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety

Xuan Zhao, Hang Zhong, Rui Wang, Dan Liu, Samuel Waxman, Linxiang Zhao, Yongkui Jing

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)5582-5596
Number of pages15
JournalOncotarget
Volume6
Issue number8
DOIs
StatePublished - 2015

Keywords

  • ABT-737
  • Acute myeloid leukemia
  • Apoptosis
  • Dihydroartemisinin
  • Noxa

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