Bota Mădălina, Fischer-Fodor Eva, Bochiș Ovidiu-Vasile, Cenariu Mihai, Popa Gheorghe, Blag Cristina Lucia, Tătaru Alexandru
Department of Pediatrics, University of Medicine and Pharmacy 'Iuliu Hațieganu', 400012 Cluj-Napoca, Romania.
Tumor Biology Department, The Oncology Institute 'I. Chiricuță', 400015 Cluj-Napoca, Romania.
Exp Ther Med. 2019 Jan;17(1):307-315. doi: 10.3892/etm.2018.6925. Epub 2018 Nov 2.
Infantile hemangioma is one of the most common benign tumors affecting children, with ~10-15% requiring medical treatment. These tumors consist of endothelial cells and stromal components, including fibroblasts, pericytes and mast cells. Effects of propranolol treatment in combination with bevacizumab or vincristine on cell growth were compared in the current study using human umbilical vein endothelial cells (HUVECs) and BJ human normal fibroblasts (BJs) to determine potential synergic effects . Inhibition of cell growth was investigated using MTT assays and cytotoxicity of the drugs in various combinations was expressed as half inhibitory concentration (IC). Apoptosis was investigated using flow cytometry, with Alexa Fluor 488 and propidium iodide. Propranolol inhibited BJ and HUVEC growth in a dose-dependent manner, with increased response observed in BJs (IC50, 148,32 µg/ml; standard error logIC50, 0.07). Treatment with vincristine induced the strongest growth inhibition in HUVECs (IC50, 17,89 µg/ml; standard error log IC50, 0.07) and BJs (IC50, 24,81 µg/ml; standard error log IC50, 0.08) compared with propranolol (HUVEC IC50, 81,94 µg/ml; standard error log IC50, 0.06; BJ-IC50, 148,32 µg/ml; standard error logIC50, 0.07) or bevacizumab (HUVEC IC50 96,91 µg/ml; standard error log IC50, 0.06; BJ IC50, 182,70 µg/ml; standard error log IC50, 0.09) alone. Bevacizumab was the weakest cytotoxic agent. Combination treatment of vincristine with bevacizumab induced the highest levels of apoptosis in HUVECs compared with all other treatments and triple-drug therapy induced the levels of apoptosis in BJs. Single treatment with vincristine, propranolol or bevacizumab induced apoptosis in BJs and HUVECs. In BJs, triple treatment exhibited the greatest influence on apoptosis, compared with single and dual treatments and in HUVECs, vincristine and bevacizumab combination treatment induced apoptosis to the highest level. The present study offers novel perspectives in drug repurposing studies for the three drugs, particularly in diseases where the pathogenesis is based on healthy endothelial cell proliferation, including hemangiomas.
婴儿血管瘤是影响儿童的最常见良性肿瘤之一，约10 - 15%需要医学治疗。这些肿瘤由内皮细胞和基质成分组成，包括成纤维细胞、周细胞和肥大细胞。在本研究中，使用人脐静脉内皮细胞（HUVECs）和BJ人正常成纤维细胞（BJs）比较了普萘洛尔联合贝伐单抗或长春新碱对细胞生长的影响，以确定潜在的协同作用。使用MTT法研究细胞生长抑制情况，并将各种组合药物的细胞毒性表示为半数抑制浓度（IC）。使用Alexa Fluor 488和碘化丙啶通过流式细胞术研究细胞凋亡情况。普萘洛尔以剂量依赖性方式抑制BJ和HUVEC的生长，在BJs中观察到反应增强（IC50，148.32μg/ml；标准误logIC50，0.07）。与普萘洛尔（HUVEC IC50，81.94μg/ml；标准误logIC50，0.06；BJ - IC50，148.32μg/ml；标准误logIC50, 0.07）或贝伐单抗（HUVEC IC50 96.91μg/ml；标准误logIC50, 0.06；BJ IC50,182.70μg/ml；标准误logIC50, 0.09）单独使用相比，长春新碱治疗在HUVECs（IC50，17.89μg/ml；标准误log IC50，0.07）和BJs（IC50，24.81μg/ml；标准误log IC50，0.08）中诱导出最强的生长抑制作用。贝伐单抗是细胞毒性最弱的药物。与所有其他治疗相比，长春新碱与贝伐单抗联合治疗在HUVECs中诱导出最高水平的细胞凋亡，三联药物疗法在BJs中诱导出细胞凋亡水平。长春新碱、普萘洛尔或贝伐单抗单药治疗在BJs和HUVECs中均诱导细胞凋亡。在BJs中，与单药和双药治疗相比，三联治疗对细胞凋亡的影响最大；在HUVECs中，长春新碱和贝伐单抗联合治疗诱导细胞凋亡至最高水平。本研究为这三种药物的药物再利用研究提供了新的视角，特别是在发病机制基于健康内皮细胞增殖的疾病中，包括血管瘤。
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