Artemisinin Inhibits Tumor Lymphangiogenesis by Suppression of Vascular Endothelial Growth Factor C

Wang, Jun; Zhang, Bicheng; Guo, Yan; Li, Guanghui; Xie, Qiang; Zhu, Bo; Gao, Jian‐Fei; Chen, Zhengtang

doi:10.1159/000148261

Cited by 41 publications

(37 citation statements)

References 52 publications

(40 reference statements)

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“…Previous studies have shown that the overexpression of VEGF can induce pericardial edema [18,24] , and our real-time PCR and in situ hybridization results also supported the notion that VEGF and its receptors play important roles in this process. In zebrafish, flk1 has an essential role in vasculogenesis, angiogenesis and hematopoiesis, which can mediate vascular dilation, endothelial cell proliferation and epidermal hyperplasia by binding VEGF [25] .…”

Section: Discussionsupporting

confidence: 88%

“…Studies with in vitro cell models, such as endothelial cells, and ex vivo models, such as the microvessel-like formation assay, indicate that DHA, along with other derivatives, can downregulate VEGF expression and inhibit angiogenesis [24,[26][27][28] . Moreover, the cytotoxicity of DHA might play a role in its anti-angiogenic function in ex vivo models inhibiting the proliferation of vessels in the medium by killing single cells.…”

Section: Discussionmentioning

confidence: 99%

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Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

Duan

Tian

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the embryotoxicity of dihydroartemisinin (DHA), the main active metabolite of artemisinin, in zebrafish, and explore the corresponding mechanisms. Methods: The embryos of wild type and TG (flk1:GFP) transgenic zebrafish were exposed to DHA. Developmental phenotypes of the embryos were observed. Development of blood vessels was directly observed in living embryos of TG (flk1:GFP) transgenic zebrafish under fluorescence microscope. The expression of angiogenesis marker genes vegfa, flk1, and flt1 in the embryos was detected using real-time PCR and RNA in situ hybridization assays. Results: Exposure to DHA (1-10 mg/L) dose-dependently caused abnormal zebrafish embryonic phenotypes in the early developmental stage. Furthermore, exposure to DHA (10 mg/L) resulted in more pronounced embryonic angiogenesis in TG (flk1:GFP) zebrafish line. Exposure to DHA (10 mg/L) significantly increased the mRNA expression of vegfa, flk1, and flt1 in the embryos. Knockdown of the flk1 protein partially blocked the effects of DHA on embryogenesis. Conclusion: DHA causes abnormal embryonic phenotypes and promotes angiogenesis in zebrafish early embryonic development, demonstrating the potential embryotoxicity of DHA.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

Duan

Tian

et al. 2013

Acta Pharmacol Sin

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“…This is further confirmed by studies of the therapeutic mechanisms in which it was clearly proved that, when compared with prednisone, Art has a better effect on controlling the serum level of IL-6 and TNF-a, inhibiting the activity of NF-kB, and down-regulating the expression of NF-kBp65 and TGF-b1 mRNA. We think that this result is concordant with the reported pharmacological functions of Art, such as immunological regulation [1][2][3][4], inhibition of cell proliferation, and induction of apoptosis [6][7][8][9][10].…”

Section: Discussionsupporting

confidence: 88%

“…In addition, other adverse factors, such as the risk of recurrence after stopping the medication, really restrain the extensive application of these treatments [13]. On the basis of these facts and previous studies [1][2][3][4][6][7][8][9][10], we proposed the possibility of using Art to treat LN. Thus, we investigated the therapeutic effect of Art on LN mice and its corresponding mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic effect of artemisinin on lupus nephritis mice and its mechanisms

Wu¹,

Zhang²,

Shi³

et al. 2010

ABBS

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In this study, we investigated the therapeutic effect of artemisinin (Art) on lupus nephritis mice and its mechanisms by comparing the differences between lupus nephritis (LN) mice given Art and control mice in molecular biology, immunohistochemistry, and histopathology. The results showed that Art could remarkably relieve the symptoms, decrease the level of urine protein/24 h, and alleviate pathological renal lesions. The differences among the four groups in the expression of the NF-kBp65 protein, nuclear factor-kB (NF-kB) activity, and the expression of transforming growth factor-b1 (TGF-b1) mRNA in renal tissue suggested that Art can lower the serum levels of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) and inhibit the expression of the NF-kBp65 protein and NF-kB and TGF-b1 mRNA in the renal tissues of LN mice. These results proved that it is reliable and effective to use Art to treat LN mice, and its therapeutic mechanisms should closely be related to the fact that Art can obviously decrease the serum levels of TNF-a and IL-6 and down-regulate the expression of the NF-kBp65 protein and NF-kB and TGF-b1 mRNA in renal tissues.

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Artemisinin dimer anticancer activity correlates with heme‐catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction

Stockwin

Han

et al. 2009

Intl Journal of Cancer

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Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anticancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1,000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the antioxidant L-NAC, the iron chelator desferroxamine and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity, whereas inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage, iron/heme and cysteine/ methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ERstress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian sarcoplasmic/endoplasmic reticulum Ca 21 -ATPases (SERCA). A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity. ' UICCKey words: artemisinin dimer; reactive oxygen species (ROS); UPR; thapsigargin; SERCA Artemisinin (Qinghaosu), a traditional Chinese medicine, is an effective chemotherapeutic for the treatment of multi-drug resistant strains of malaria. 1-3 More recently, semi-synthetic derivatives have been shown to have anticancer activity. 4-6 Cancer cells exposed to artemisinin derivatives demonstrate decreased proliferation, increased levels of oxidative stress, induction of apoptosis and inhibition of angiogenesis. Whereas monomeric forms have activity in the nanomolar range for treatment of malaria, activity versus tumor cells is in the upper micromolar range. Conversion of artemisinin to dimeric and trimeric forms was also shown to substantially enhance anticancer activity. 5,6 The mechanism underlying pharmacological activity in both malaria and cancer is still the subject of debate. 7,8 In malaria, the classical mechanism is thought to involve reaction of the endoperoxide bridge with free heme-iron liberated during degradation of hemoglobin inside the parasite food vacuole. 9 Endoperoxide cleavage generates damaging reactive oxygen species (ROS) and carbon-centered radicals leading to parasite death. However, recent work suggests that artemisinins may also function as in...

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Artemisinin Inhibits Tumor Lymphangiogenesis by Suppression of Vascular Endothelial Growth Factor C

Cited by 41 publications

References 52 publications

Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

Therapeutic effect of artemisinin on lupus nephritis mice and its mechanisms

Artemisinin dimer anticancer activity correlates with heme‐catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction

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