Llorens de Los Ríos María C, Lanza Priscila A, Barbieri Cecilia L, González María L, Chabán Macarena Funes, Soria Gastón, Vera D Mariano A, Carpinella María C, Joray Mariana B
Fundación para el Progreso de la Medicina, Córdoba, Argentina.
Department of Chemistry and Biochemistry, QUIAMM-INBIOTEC-CONICET, College of Exact and Natural Sciences, Universidad Nacional de Mar del Plata, Mar del Plata, Argentina.
Front Pharmacol. 2022 Oct 12;13:1007790. doi: 10.3389/fphar.2022.1007790. eCollection 2022.
Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and β2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Among the plants screened, , showed an outstanding effect with an IC of 33.6 ± 3.4 μg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC of 2.7 ± 0.4 μM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 μM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and β2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.
肿瘤血管生成被认为是癌症的一个关键病理特征，在多药耐药性（MDR）中起关键作用。目前可用药物的不良反应以及对这些药物的耐药性发展仍然是最难克服的障碍。这项工作探索了来自阿根廷的植物群，作为具有抗血管生成活性的新化学实体的来源。使用牛主动脉内皮细胞（BAECs）进行的管形成试验是评估抗血管生成活性的首选实验。通过Transwell迁移试验研究了纯化合物对细胞侵袭性的影响。通过分子和大规模动态模拟研究了纯化合物对VEGFR-2以及PKC同工酶α和β2激活的抑制作用。分别通过MTT和溶血试验评估对外周血单核细胞和红细胞的细胞毒性。使用SwissADME在线工具进行药理性质（ADME）预测和类药特性评估。在所筛选的植物中， 显示出显著效果，IC为33.6±3.4μg/ml。生物导向分离得到其活性代谢物三联噻吩α-三联噻吩甲醇。该化合物抑制VEGF诱导的管形成，IC为2.7±0.4μM，当在10μM下测试时，显著损害牛主动脉内皮细胞（BAECs）以及高侵袭性乳腺癌细胞MDA-MB-231的侵袭性。通过大规模分子动力学模拟探索了直接的VEGFR-2和PKC抑制作用。获得的结果证实了对蛋白激酶C（PKC）同工酶α和β2的抑制作用是其抗血管生成活性的主要机制。α-三联噻吩甲醇对外周血单核细胞和红细胞没有毒性证据。这些发现支持这种噻吩作为一种有前景的抗血管生成植物化学物质，可对抗几种类型的癌症，主要是那些具有MDR表型的癌症。
