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.

Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells

“…The cytotoxic mechanisms of DHA have been investigated in several studies, showing that dihydroarteminin enhances cell apoptosis via its effects on the ERK signaling pathway in endothelial cells (14), inactivating NF-κB in pancreatic cancer (16) and by upregulation of Noxa by promotion of FOXO3a expression in acute myeloid leukemia cells (23). Additionally, DHA exerts an antineoplastic effect in prostate cancer cells by increasing death receptor 5 expression (24) and induces NOXA-dependent mitochondrial cell apoptosis in melanoma cells with upregulation of cellular oxidative stress (25), furthermore, DHA triggers cell cycle arrest via effects on the AKT/GSK3β/cyclin D1 pathway in A549 lung cancer cells (26).…”

Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells

“…Furthermore, DHA was identified to prevent breast cancer-induced osteolysis via inhibiting breast cancer cells and osteoclasts (26). For leukemia treatment, DHA can induce autophagy and inhibit the growth of iron-loaded human myeloid leukemia K562 cells via reactive oxygen species toxicity (27); DHA and its derivative induce apoptosis in acute myeloid leukemia cells through the Noxa-mediated pathway, requiring iron and an endoperoxide moiety (28). However, the effect of DHA on AMoL has yet to be fully elucidated.…”

DHA is a newly defined STAT3 inhibitor that may be of multiple potential uses in cancer treatment

“…Apart from antimalarial and anti-schistosomiasis [26] activities, DHA has been shown to exhibit inhibitory effects against erythematous lupus [27] , inflammatory diseases [28] , bacteria [29] and viruses [30] . However, another conspicuous property of DHA resides on its potent antitumor activities against a variety of human cancer cells, such as lung carcinoma [31] , breast cancer [32] , hepatocellular carcinoma [33] , osteosarcoma [34] , acute myeloid leukemia [35] and cervical cancer [36] , etc.…”

“…We believe that DHA has three dominant advantages over other chemotherapeutic agents: (I) well-understood clinical pharmacokinetics and pharmacodynamics based on its long-term and frontline clinical applications for antimalarial purposes; (II) firmly established large-scale production of DHA, which is beneficial to decrease the cost of chemotherapy; (III) potent antitumor efficacies, negligible adverse effects and easy solubility in water, encouraging its practical uses in cancer treatment. The anti-cancer effects of DHA have been proposed to be mediated through generating reactive oxygen species (ROS) and NOXA [35,37] , reducing PKCα/Raf/ERK and JNK activities [38] , and decreasing NF-κB DNA binding [39] and MEK/ERK signaling pathway [40] . However, all of before-mentioned molecular understandings referring to the pan-pathway inhibitory effects on cancer cells are insufficient to explain the peculiar part of tumor inhibition borne by DHA, which deserves further investigation.…”