Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice

Abstract

AIM:To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells. METHODS:The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy. SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using flow cytometry. RESULTS:The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was significantly lower in arsenic-treated mice than in the control group. The fluorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3-treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higher than that in the controls. CONCLUSION:Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.

Matrix Metalloproteinase Activity Causes VEGFR‐2 Cleavage and Microvascular Rarefaction in Rat Mesentery

“…The current results suggest that cleavage of VEGFR-2 by MMPs occurs in the same mesenteric tissue, which in the SHR is associated with microvascular rarefac- tion, dysfunction, and endothelial apoptosis. Cleavage of the extracellular domain reduces the ability of the cell to bind VEGF agonists and may be one of the reasons for the enhanced apoptosis in the SHR endothelium [10,12,23,25]. The functional effect of attenuated VEGFR-2 signaling on vessel loss is supported by observation of reduced VEGFR-2 protein levels being associated with impaired angiogenesis in the SHR [24].…”

Arsenic Trioxide Decreases Lymphangiogenesis by Inducing Apoptotic Pathways and Inhibition of Important Endothelial Cell Receptors

“…ATO is a chemotherapy drug and exhibits low toxicity when used in the treatment of APL [2]. ATO has been shown to induce anti-lymphangiogenic activity in a mouse model of gastric cancer by various mechanisms, including the downregulation of pro-lymphangiogenic factors such as VEGFR-3 and VEGF-C in cancer cells [19]. In addition, it has been demonstrated that ATO impairs angiogenesis in vitro and in vivo [16,28,29].…”

“…Thus, targeting tumor lymphangiogenesis may provide a promising approach to treat cancer metastasis. The first evidence in a gastric cancer model revealed that As 2 O 3 may inhibit lymphangiogenesis by suppressing the expression of VEGF-C and VEGFR-3 in gastric cancer cells [19]. Based on these findings, we investigated the anti-lymphangiogenic effects of ATO in primary human lymphatic endothelial cells.…”

Arsenic trioxide-increased MDCK cells proliferation requires activator protein 1-mediated increase of the sodium/proton exchanger 1 activity

“…The cell suspension was mixed in 150 mL DMSO and the absorbance at 492 nm was measured in a microplate reader (Multiskan EX Microplate Photometer, model 355, Thermo-Labsystems, Shanghai, China). The percentage of viable cells was calculated as described [21]. Cell viability was ~98% in the absence or presence of ATO (not shown).…”

“…t = 0 h), and e is 2.7182. The K values were expressed as the number of cells x10 3 per cm 2 of cell culture surface per hour [4,21]. Doubling time (Dt) for cell growth was derived from 0.6932/K and was expressed in hours.…”