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In silico prediction of targets for anti-angiogenesis and their in vitro evaluation confirm the involvement of SOD3 in angiogenesis.

ABSTRACT: Biocomputational network approaches are being successfully applied to predict and extract previously unknown information of novel molecular components of biological systems. In the present work, we have used this approach to predict new potential targets of anti-angiogenic therapies. For experimental validation of predictions, we made use of two in vitro assays related to two key steps of the angiogenic process, namely, endothelial cell migration and formation of "tubular-like" structures on Matrigel. From 7 predicted candidates, experimental tests clearly show that superoxide dismutase 3 silencing or blocking with specific antibodies inhibit both key steps of angiogenesis. This experimental validation was further confirmed with additional in vitro assays showing that superoxide dismutase 3 blocking produces inhibitory effects on the capacity of endothelial cells to form "tubular-like" structure within type I collagen matrix, to adhere to elastin-coated plates and to invade a Matrigel layer. Furthermore, angiogenesis was also inhibited in the en vivo aortic ring assay and in the in vivo mouse Matrigel plug assay. Therefore, superoxide dismutase 3 is confirmed as a putative target for anti-angiogenic therapy.

SUBMITTER: Garcia-Vilas JA

PROVIDER: S-EPMC5915121 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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In silico prediction of targets for anti-angiogenesis and their in vitro evaluation confirm the involvement of SOD3 in angiogenesis.

García-Vilas Javier A JA Morilla Ian I Bueno Anibal A Martínez-Poveda Beatriz B Medina Miguel Ángel MÁ Ranea Juan A G JAG

Oncotarget 20180403 25

Biocomputational network approaches are being successfully applied to predict and extract previously unknown information of novel molecular components of biological systems. In the present work, we have used this approach to predict new potential targets of anti-angiogenic therapies. For experimental validation of predictions, we made use of two in vitro assays related to two key steps of the angiogenic process, namely, endothelial cell migration and formation of "tubular-like" structures ...[more]

PMID: 29707113

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Project description:BackgroundBreast cancer is currently the world's most predominant malignancy. In cancer progression, angiogenesis is a requirement for tumor growth and metastasis.Alpinumisoflavone (AIF), a bioactive isoflavonoid, exhibited good binding affinity with the angiogenesis pathway's druggable target through molecular docking.ObjectivesTo confirm AIF's angiogenesis inhibitory activity, cytotoxic potential toward breast cancer cells, and druggability.MethodsAntiangiogenic activity was evaluated in six pro-angiogenic proteins in vitro, duck chorioallantoic membrane (CAM) in ovo, molecular docking and druggability in silico.ResultsFindings showed that AIF significantly inhibited (p = < 0.001) the HER2(IC50 = 2.96 µM), VEGFR-2(IC50 = 4.80 µM), MMP-9(IC50 = 23.00 µM), FGFR4(IC50 = 57.65 µM), EGFR(IC50 = 92.06 µM) and RET(IC50 = > 200 µM) activity in vitro.AIF at 25 µM-200 µM significantly inhibited (p = < 0.001) the total number of branch points (IC50 = 14.25 μM) and mean length of tubule complexes (IC50 = 3.52 μM) of duck CAM comparable (p = > 0.001) with the positive control 200 µM celecoxib on both parameters.AIF inhibited the growth of the estrogen-receptor-positive (ER +) human breast cancer cells (MCF-7) by 44.92 ± 1.79% at 100 µM while presenting less toxicity to human dermal fibroblast neonatal (HDFn) normal cells.The positive control 100 µM doxorubicin showed 86.66 ± 0.93% and 92.97 ± 1.27% inhibition with MCF-7 (IC50 = 3.62 μM) and HDFn, (IC50 = 27.16 μM) respectively.In docking, AIF has the greatest in silico binding affinity on HER2 (-10.9 kcal/mol) among the key angiogenic molecules tested. In silico rat oral LD50 calculation indicates that AIF is moderate to slightly toxic at 146.4 mg/kg with 1.1 g/kg and 20.1 mg/kg upper and lower 95% confidence limits. Lastly, it sufficiently complies with Lipinski's, Veber's, Egan's, Ghose's, and Muegge's Rule, supporting its oral drug-like property.ConclusionThis study revealed that AIF possesses characteristics of a phytoestrogen compound with significant binding affinity, inhibitory activity against pro-angiogenic proteins, and cytotoxic potential against ER + breast cancer cells.The acceptable and considerable safety and drug-likeness profiles of AIF are worthy of further confirmation in vivo and advanced pre-clinical studies so that AIF can be elevated as a promising molecule for breast cancer therapy.

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In silico prediction of targets for anti-angiogenesis and their in vitro evaluation confirm the involvement of SOD3 in angiogenesis.

Publications

<i>In silico</i> prediction of targets for anti-angiogenesis and their <i>in vitro</i> evaluation confirm the involvement of SOD3 in angiogenesis.

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