Dihydroartemisinin targets VEGFR2 via the NF-κB pathway in endothelial cells to inhibit angiogenesis

Fang, Dong; Zhou, Xia; Li, Changsheng; Yan, Shi Fang; Deng, Xianming; Zhi-qun, Cao; Li, Liqun; Tang, Bo; Allen, T. C.; Liu, Ju

doi:10.4161/15384047.2014.955728

Cited by 75 publications

(68 citation statements)

References 46 publications

(53 reference statements)

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“…NF-κB was a direct regulator of VEGFR2 in the neonatal pulmonary vasculature and its inhibition decreased angiogenesis [29]. Pro-angiogenic properties of NF-κB have been reported in other disease models [30] [31] [32]. We show in our study that the NF-κB pathway activation is greater in female HUVECs compared to male with greater expression of IKKβ, p-IKbα and greater level of p65 activation.…”

Section: Discussionsupporting

confidence: 74%

Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells

Zhang

Lingappan

2017

Biochemical and Biophysical Research Communications

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Despite the well-established sex-specific differences in the incidence of bronchopulmonary dysplasia (BPD), the molecular mechanism(s) behind these are not completely understood. Pulmonary angiogenesis is critical for alveolarization and arrest in vascular development adversely affects lung development. Human neonatal umbilical vein endothelial cells (HUVECs) provide a robust in vitro model for the study of endothelial cell physiology and function. Male and Female HUVECs were exposed to room air (21% O2, 5% CO2) or hyperoxia (95% O2, 5% CO2) for up to 72 hr. Cell viability, proliferation, H2O2 production and angiogenesis were analyzed. Sex-specific differences in the expression of VEGFR2 and modulation of NF-kappa B pathway were measured. Male HUVECs have decreased survival, greater oxidative stress and impairment in angiogenesis compared to similarly exposed female cells. There is differential expression of VEGFR2 between male and female HUVECs and greater activation of the NF-kappa B pathway in female HUVECs under hyperoxic conditions. The results indicate that sex differences exist between male and female HUVECs in vitro after hyperoxia exposure. Since endothelial dysfunction has a major role in the pathogenesis of BPD, these differences could explain in part the mechanisms behind sex-specific differences in the incidence of this disease.

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Section: Discussionsupporting

confidence: 74%

Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells

Zhang

Lingappan

2017

Biochemical and Biophysical Research Communications

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“…In cultured endothelial cells, DHA inhibits proliferation, migration and tube formation (26)(27)(28). In a mouse model of retinal neovascularization, intravitreal injection of DHA reduced angiogenesis (24). As a widely used anti-malarial drug, DHA has been proven to be safe with minimal side effects and may be used clinically as a component of cancer chemotherapy (29).…”

Section: Introductionmentioning

confidence: 99%

“…DHA has also demonstrated strong anti-tumor activity (23). Recently, DHA emerged as a promising agent with potent anti-angiogenic properties (24). DHA represses the expression of VEGF in several cancer cell lines (23,25).…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin transiently activates the JNK/SAPK signaling pathway in endothelial cells

et al. 2016

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Abstract. Artemisinin and its derivatives are well-known anti-malaria drugs and in the early stages of research for cancer treatment. Dihydroartemisinin (DHA), a more water-soluble derivative of artemisinin, has demonstrated strong anti-angiogenic activity. The purpose of the present study was to investigate the underlying molecular mechanisms of the effect of DHA on angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for apoptosis and activation of the c-Jun N-terminal kinase (JNK) signaling pathway, one of the major mitogen-activated protein kinase cascades. It was observed that 20 µM DHA induces transient activation of JNK in HUVECs. DHA also elevates the expression of cyclooxygenase-2 and matrix metalloproteinase-13, which is abolished by treatment with the JNK inhibitor SP600125. Although DHA persistently increases inhibitor of κB-α protein and thus inhibits nuclear factor-κB signaling, it does not affect apoptosis or caspase 3/9 activities in HUVECs. The present study provides key information for understanding the effects of DHA on endothelial cells, which is required for investigating its potential for clinic application as a chemotherapeutic agent.

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“…It has been recommended by the World Health Organization as a first line anti-malarial therapy [4]. In addition to its potent anti-malarial activity, emerging studies have shown that DHA may also be a potential chemopreventive drug, exhibiting strong antitumor activity in various human cancer cells by blocking cell proliferation [5], arresting cell cycle [6], promoting apoptosis [7], and inhibiting angiogenesis and metastasis [8, 9]. In addition, DHA can potentiate the anticancer effect of chemotherapeutic agents and photodynamic therapy to induce cell apoptosis in various kinds of cancers [10-13].…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Zhao

Pan

et al. 2017

Cell Physiol Biochem

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Background/Aim: Women with advanced ovarian carcinoma are less likely to receive platinum-based chemotherapy and surgery due to a greater risk of cytotoxicity and poorer outcomes. We attempted to improve a promising therapy against ovarian cancer by using a combination of dihydroartemisinin (DHA) and curcumin (Cur). Methods: Human ovarian cancer SKOV3 cells were treated with DHA, Cur alone, or a combination of both. The viability of SKOV3 cells was measured by Cell Counting Kit-8 (CCK-8) and a colony formation assay. The cell cycle and apoptosis of SKOV3 cells were monitored by flow cytometry. The mRNA and protein expression levels of target genes were respectively examined by qRT-PCR and western blot. The biological effects of miR-124 on midkine (MK) were verified by a luciferase activity analysis. Results: Combined treatment of DHA and Cur synergistically decreased cell viability, arrested cell cycle, and promoted apoptosis in SKOV3 cells. Moreover, it significantly attenuated the expression of oncogene MK and synergistically upregulated the expression of miR-124. Furthermore, miR-124 was verified to bind directly to the 3ʹ-untranslated region of MK mRNA, resulting in mRNA degradation and reduced MK protein levels. The combination of DHA with Cur significantly inhibited tumor growth in xenograft nude mice without obvious toxicity. Conclusion: Co-treatment with DHA and Cur exhibited a synergistic anti-tumor effect on SKOV3 cells both in vitro and in vivo.

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Dihydroartemisinin targets VEGFR2 via the NF-κB pathway in endothelial cells to inhibit angiogenesis

Cited by 75 publications

References 46 publications

Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells

Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells

Dihydroartemisinin transiently activates the JNK/SAPK signaling pathway in endothelial cells

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

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