RESUMEN
OBJECTIVE: Angiogenesis plays a dominant role in many pathophysiologic disorders, including cancer. Tranilast, which is an anti-fibrotic drug, is also suggested as an anti-angiogenesis agent. As Teucrium polium (TP) is known as an herbal medicine with antitumor properties, this study aimed to investigate the effects of TP and Tranilast on human umbilical vein endothelial cells (HUVECs), in vitro model of angiogenesis, as well as rat's aortic ring ex vivo model. METHODS: In this study, The HUVECs were treated with various doses of TP and Tranilast each one alone or in combination together. Cell survival test, aortic ring ex-vivo assay, and evaluating mRNA expressions of VEGFA and TGF-ß ligands and receptors were performed. RESULTS: The survival rate of HUVECs has significantly (p <0.05) reduced by TP and Tranilast. The combination of both TP and Tranilast significantly reduced cell viability as compared to the administration of TP or Tranilast alone. As well, the treatment of HUVECs with TP and/or Tranilast significantly (p <0.05) decreased TGF-ß1, TGF-ß 2, TGF-ßRI, and TGF-ßRII mRNA expression levels, but not the expression of TGF-ß3 and TGF-ßRIII in the TP-treated cells. Image analysis showed that TP and/or Tranilast inhibited vascular growth in the aortic ring assay. CONCLUSION: Our results strongly support the anti-angiogenic effects of the TP and Tranilast combination on both in vitro and ex vivo models of angiogenesis. However, further investigations in in vivo models and human studies are needed before human use.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Fibrina/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Extractos Vegetales/farmacología , Teucrium/química , ortoaminobenzoatos/farmacología , Inhibidores de la Angiogénesis/química , Animales , Antiinflamatorios no Esteroideos/farmacología , Sinergismo Farmacológico , Quimioterapia Combinada , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Masculino , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ratas , Ratas Sprague-Dawley , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , ortoaminobenzoatos/químicaRESUMEN
Purpose: Angiogenesis plays an important role in numerous pathophysiological events like cancer. As a result of this, tranilast as an anti-fibrotic drug induces the promising antitumor activities through the inhibition of angiogenesis. Further, Teucrium polium (TP) is a herbal medicine (family Lamaceae) with antitumor properties. This study was conducted to investigate the combination effects of tranilast and T. polium on human umbilical vein endothelial cells (HUVECs) viability and apoptotic genes expression. Methods: The HUVECs line was treated using different doses of tranilast and T. polium alone or their combination. The cell cytotoxicity was evaluated using MTT and LDH assays; apoptosis was examined using acridine orange/ethidium bromide staining, nitric oxide (NO) production was evaluated using Griess reaction and the expression of BAX and BCL-2 genes were detected using real-time RT-PCR. One-way analysis of variance (ANOVA) test was used to compare the data in different groups. Results: The survival rate of HUVECs was significantly reduced (p<0.05) in a dose dependent manner by tranilast and T. polium. However, T. polium and tranilast combination significantly (p<0.001) reduced cell viability and increased apoptotic cells as compared to each drug alone. Also, HUVECs treated with Tranilast / T. polium combination showed a reduced level of NO as regards to cells exposed only to Tranilast or T. polium (p<0.05). Furthermore, a significant increase in BAX and a decrease in BCL-2 mRNA expression were observed in combination group (p<0.001). Conclusion: T. polium synergistically increased the antiangiogenic effect of tranilast on in vitro angiogenic model of HUVECs.