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

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

doi:10.18632/oncotarget.3336

Xuan Zhao, Yongkui Jing + Show 5 more

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https://doi.org/10.18632/oncotarget.3336

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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.

Highlights

Acute myeloid leukemia is a disease of malignant proliferation of hematopoietic cells with disrupted differentiation and apoptotic program
HL-60 cells were treated with several concentrations of DHA or X-11 for 12, 18 and 24 h and apoptotic cells were measured based on morphological changes after staining with acridine orange (AO) and ethidium bromide (EB)
Altered levels of cleaved PARP in cells treated with DHA and X-11 corresponded to levels of cleaved caspase-3, caspase-8 and caspase-9, suggesting that all three caspases participated in apoptosis induction (Fig. 1D)

Summary

Introduction

Acute myeloid leukemia is a disease of malignant proliferation of hematopoietic cells with disrupted differentiation and apoptotic program. Molecular and cellular genetic analyses in AML revealed many potential signaling pathways which have been used to develop therapeutic agents [1, 2], but so far only limited clinic activities have been achieved [3, 4]. It seems that agents selectively inducing cell death would be more effective for AML treatment. Mitochondrialmediated apoptosis, controlled by the anti-apoptotic protein Bcl-2 family, Bcl-2, Bcl-xL and Mcl-1 [5], was thought to be the main mechanism of AML cell killing by chemotherapy. Molecular studies revealed that Mcl-1 plays an even more important role than Bcl-2/ Bcl-xL in protecting AML cells from apoptosis [11] and, agents inhibiting Mcl-1 need to be developed

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