Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species

Lu, Jin‐Jian; Meng, Linghua; Cai, Yujun; Chen, Qin; Tong, Linjiang; Lin, Liping; Ding, Jian

doi:10.4161/cbt.7.7.6035

Cited by 108 publications

(89 citation statements)

References 29 publications

(46 reference statements)

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“…The mechanism of endoperoxide-induced apoptotic cell death via ROS generation, mitochondrial membrane depolarization, caspase-3 and -7 activation, and DNA degradation has been well characterized in several cell types (17)(18)(19). Nevertheless, crucial information defining the primary cellular target of cytotoxicity and the exact intracellular mechanism of chemical activation remains unclear.…”

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confidence: 99%

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

Mercer

Copple

Maggs

et al. 2011

Journal of Biological Chemistry

142

127

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confidence: 99%

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

Mercer

Copple

Maggs

et al. 2011

Journal of Biological Chemistry

142

127

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“…In addition, the type of derivative was proved to target G 1 phase of the cell cycle [41] . Thus far, antitumor activity of artemisinins and the underlying mechanisms have been www.nature.com/aps Li Y Acta Pharmacologica Sinica npg widely studied [43][44][45][46][47][48][49] , however, few clinical trials were reported. Antimalarial chloroquine was used as immunosuppressive agent.…”

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confidence: 99%

Qinghaosu (artemisinin): Chemistry and pharmacology

2012

Acta Pharmacol Sin

119

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Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug. Up to now, some important progresses of Qinghaosu research have been made, including synthesis of new Qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions. The present review briefly describes these efforts made by researchers in China, particularly in this Institute.Keywords: Qinghaosu; artemisinin; structure modification; antimalarial activity; anticancer activity; immunosuppressive activity; mode of action Acta Pharmacologica Sinica (2012) 33: 1141-1146; doi: 10.1038/aps.2012.104; published online 27 Aug 2012On 23rd May 1967, China established National Steering Group on antimalarial drug research, more than 60 institutes and 500 researchers joined in this project. After screening of over 5000 traditional Chinese medicines, Qinghaosu (QHS), an antimalarial principle, was isolated from Artemisia annua L in 1972 [1,2] . At the end of 1975, its unique chemical structure was elucidated, as a sesquiterpene lactone bearing a peroxy group, quite different from that of all known antimalarial drugs [3] .Early pharmacological and clinic studies showed QHS have rapid onset of action, low toxicity and high effect on both drug-resistant and drug-sensitive malaria. However, its shortcomings (poor solubility in water or oil; high rate of parasite recrudescence) needed to be overcome. In 1976, our Institute was charged with this important mission, and a research in relationship between chemical structure and activity immediately started.First of all, the function of peroxy group for antimalarial activity was examined. The negative result of deoxyqinghaosu (Scheme 1) against P berghei in mice demonstrated that the peroxy group was essential. Soon afterwards, it was found that some other simple peroxides including monoterpene ascaridol had no antimalarial activity. These experimental results proved peroxy group to be an essential but not a sufficient factor. At that time, we noted the molecule contained a rare segment -O-C-O-C-O-C=O, and realized that whole molecular skeleton might play an important role for antimalarial activity.When dihydroartemisinin (DHA) was found to be more active than QHS, but was still with poor solubility and lower stability (as a lactol) than QHS, we decided to prepare its derivatives. In 1976-1977, over 50 derivatives of DHA were synthesized (Scheme 1) and evaluated [4,5] .The first 25 compounds (in oil solution) were tested in mice infected chloroquine-resistant P berghei though intramuscular injection [6] . Most of these derivatives showed higher activity than QHS (SD 50 6.20 mg/kg) and DHA (SD 50 3.65 mg/kg). In the ether series, SM 224 (R=CH 3 , SD 50 1.02 mg/kg) is more

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“…In the time course study, 20 µM DHA induced a significant reduction of ERK1/2 phosphorylation and expression. It has been reported that DHA prevented phosphorylation of ERK1/2 and other components of MAPK cascades in specific cell types (18,19). As the activation of the Ras-ERK cascade leading to endothelial cell proliferation and survival during angiogenesis (28), DHA may inhibit this cascade to reduce cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…In human monocytic THP-1 cells, artemisinin blocked the phosphorylation of JNK, ERK1/2 and p38 MAPK (18). In HL-60 leukemia cells, DHA induced apoptosis through activation of p38 MAPK, but not JNK or ERK1/2 (19). In endothelial cells cultured with VEGF, DHA failed to increase the activation of p38 pathway (20).…”

Section: Introductionmentioning

confidence: 94%

Dihydroartemisinin inhibits endothelial cell proliferation through the suppression of the ERK signaling pathway

et al. 2015

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Abstract. Disrupting tumor angiogenesis serves as an important strategy for cancer therapy. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has exhibited potent anti-angiogenic activity. However, the molecular mechanisms underlying this effect have not been fully understood. The present study aimed to investigate the role of DHA on endothelial cell proliferation, the essential process in angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for proliferation, apoptosis and activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Proliferation of HUVECs was inhibited by 20 µM DHA without induction of apoptosis. DHA also reduced the phosphorylation of ERK1/2, and downregulated the mRNA and protein expression of ERK1/2 in HUVECs. In addition, DHA suppressed the transcription and protein expression of ERK1/2 downstream effectors c-Fos and c-Myc. Electrical cell-substrate impedance sensing real-time analysis demonstrated that ERK signaling inhibitor PD98059 comprises the anti-proliferative effects of DHA. Thus, DHA inhibits endothelial cell proliferation by suppressing the ERK signaling pathway. The present study strengthened the potential of DHA as an angiogenesis inhibitor for cancer treatment.

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Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species

Cited by 108 publications

References 29 publications

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

Qinghaosu (artemisinin): Chemistry and pharmacology

Dihydroartemisinin inhibits endothelial cell proliferation through the suppression of the ERK signaling pathway

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