Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

Yang, Mian; Chang, Ke-Jie; Zheng, Jin-Cheng; Huang, Hai; Sun, Guangyuan; Zhao, Xuewei; Li, Bing; Xiu, Qingyu

doi:10.3892/ol.2017.6518

Cited by 23 publications

(15 citation statements)

References 48 publications

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“…The effect of W on stem/precursor cell growth does not follow a linear dose-response but rather an inverted U-shaped hormetic model (Calabrese 2004) (Fig. 1), as previously described for other metals such as As, Cd, Cu and Hg (Damelin et al 2000, Hao et al 2009 and specifically reported in embryonic cells of other tissues: human embryo lung fibroblasts for As (Yang et al 2017) and human embryonic kidney 293 cells (HEK 293) for Cd and Hg (Jiang et al 2018). In parallel experiments, we observed that staurosporine-induced apoptosis was more than 30% reduced in thyrospheres exposed to Na 2 WO 4 but again, no effect was observed on mature thyrocyte apoptosis (Fig.…”

Section: :8supporting

confidence: 64%

Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Gianì

Pandini

Scalisi

et al. 2019

Endocrine-Related Cancer

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Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

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Section: :8supporting

confidence: 64%

Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Gianì

Pandini

Scalisi

et al. 2019

Endocrine-Related Cancer

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“…We previously reported that As 2 O 3 inhibited the proliferation and colony formation of SCLC cell line [24,25]. Other researchers also reported that As 2 O 3 inhibited the migration and invasion of lung cancer and other solid tumor cells [26–28].…”

Section: Introductionmentioning

confidence: 97%

“…In addition, we demonstrated that As 2 O 3 inhibited the growth of lung cancer xenografts, and the inhibitory effect in SCLC was particularly obvious. It was also revealed that As 2 O 3 inhibited angiogenesis in SCLC by downregulating VEGF; As 2 O 3 also influenced the ultrastructure of the endothelial cells and the formation of neovascular lumen by blocking the Dll4-Notch pathway [23,24]. However, whether As 2 O 3 can inhibit the metastasis of SCLC and the possible mechanism involved is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling

et al. 2019

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Background The inhibitory effect of arsenic trioxide (As 2 O 3 ) on lung cancer has been reported in some preclinical studies. However, its effect on small cell lung cancer (SCLC) has been poorly explored. Calcineurin and its substrate, nuclear factor of activated T cells (NFAT), mediate the downstream signaling of VEGF, and is critical in the process endothelium activation and tumor metastasis. In this study, we aimed to evaluate whether As 2 O 3 had inhibitory effects on endothelial cells activation and the metastasis of SCLC, and to explore the possible mechanisms. Material/Methods In vitro , human umbilical vein endothelial cells (HUVECs) were used. Cell Counting Kit-8 assay and cell migration assay were performed to determine the effect of As 2 O 3 on HUVECs proliferation and migration. The level of calcineurin, NFAT, downstream factors for Down syndrome candidate region 1 (DSCR1), and the endogenous inhibitor of calcineurin, were evaluated by quantitative PCR and western blotting. In vivo , SCLC metastasis models were established by injecting NCI-H446 cells into tail veins of nude mice. Tumor-bearing mice were treated with As 2 O 3 or calcineurin inhibitor for 10 days, after which tumor metastasis in target organs was evaluated. Results As 2 O 3 significantly inhibited the proliferation and migration of endothelial cells. Also, As 2 O 3 inhibited the expression levels of calcineurin, NFAT, and the downstream target genes CXCR7 and RND1, while it upregulated the level of DSCR1. Both As 2 O 3 and calcineurin inhibitor exhibited notable inhibitory effect on the metastasis of SCLC, without obvious side effects. Conclusions These findings suggested that As 2 O 3 had remarkable inhibitory effects on the endothelial cell activation and SCLC metastasis, and the mechanism might be related to the blocking of calcineurin-NFAT signaling by upregulating DSCR1.

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“…As 2 O 3 not only reduced MVD but also influenced the morphology of blood vessels by inducing the formation of irregular vascular structures with narrow and tortile lumens. Our previous study showed that As 2 O 3 inhibited angiogenesis in lung cancer via the downregulation of VEGF signaling [18, 19] and was accountable for the reduction in microvessels. However, we were unable to explain the change in vessel morphology.…”

Section: Discussionmentioning

confidence: 99%

“…We found that As 2 O 3 significantly reduced microvessel density (MVD) and induced poor development of vascular structures in NCI-H446 cell xenograft models [18]. We also demonstrated that As 2 O 3 restricted the tube formation ability of endothelial cells in vitro [19]. As the effects of As 2 O 3 on angiogenesis regulation were similar to those observed with the blockade of the Notch pathway, we suggest that this pathway may be the antiangiogenic target of As 2 O 3 .…”

Section: Introductionmentioning

confidence: 99%

Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer

Yang

Chang

et al. 2019

BioMed Research International

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Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As2O3) was reported to exert antiangiogenesis activities against lung cancer and induce poor development of vessel structures, similar to the effect observed following the blockade of Notch signaling. However, there are no direct evidences on the inhibitory effects of As2O3 on tumor growth and angiogenesis via blockade of Notch signaling in SCLC. Here, we found that As2O3 significantly inhibited the tumor growth and angiogenesis in SCLC and reduced the microvessel density. As2O3 disturbed the morphological development of tumor vessels and downregulated the protein levels of delta-like canonical Notch ligand 4 (Dll4), Notch1, and Hes1 in vivo. DAPT, a Notch signaling inhibitor, exerted similar effects in SCLC. We found that both As2O3 treatment and Notch1 expression knockdown resulted in the interruption of tube formation by human umbilical vein endothelial cells (HUVECs) on Matrigel. As2O3 had no effects on Dll4 level in HUVECs but significantly inhibited the expression of Notch1 and its downstream gene Hes1 regardless of Dll4 overexpression or Notch1 knockdown. These findings suggest that the antitumor activity of As2O3 in SCLC was mediated via its antiangiogenic effect through the blockade of Notch signaling, probably owing to Notch1 targeting.

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Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

Cited by 23 publications

References 48 publications

Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling

Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer

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