Alfei Silvana, Marengo Barbara, Zuccari Guendalina, Turrini Federica, Domenicotti Cinzia
Department of Pharmacy (DiFAR), University of Genoa, Viale Cembrano, 16148 Genoa, Italy.
Department of Experimental Medicine-DIMES, University of Genoa, Via Alberti L.B., 16132 Genoa, Italy.
Nanomaterials (Basel). 2020 Jun 26;10(6):1243. doi: 10.3390/nano10061243.
Human neuroblastoma (NB), a pediatric tumor inclined to relapse, after an initial response to therapy, usually develops resistance. Since several chemotherapeutics exert anticancer effect by increasing reactive oxygen species (ROS), NB cells overproduce antioxidant compounds becoming drugs-resistant. A strategy to sensitize NB cells to chemotherapy involves reducing their antioxidant defenses and inducing ROS overproduction. Concerning this, although affected by several issues that limit their clinical application, antioxidant/pro-oxidant polyphenols, such as gallic acid (GA), showed pro-oxidant anti-cancer effects and low toxicity for healthy cells, in several kind of tumors, not including NB. Herein, for the first time, free GA, two GA-dendrimers, and the dendrimer adopted as GA reservoir were tested on both sensitive and chemoresistant NB cells. The dendrimer device, administered at the dose previously found active versus sensitive NB cells, induced ROS-mediated death also in chemoresistant cells. Free GA proved a dose-dependent ROS-mediated cytotoxicity on both cell populations. Intriguingly, when administered in dendrimer formulations at a dose not cytotoxic for NB cells, GA nullified any pro-oxidant activity of dendrimer. Unfortunately, due to GA, nanoformulations were inactive on NB cells, but GA resized in nanoparticles showed considerable ability in counteracting, at low dose, ROS production and oxidative stress, herein induced by the dendrimer.
人类神经母细胞瘤（NB）是一种易于复发的儿科肿瘤，在对治疗产生初始反应后，通常会产生耐药性。由于几种化疗药物通过增加活性氧（ROS）发挥抗癌作用，NB细胞会过度产生抗氧化化合物，从而产生耐药性。使NB细胞对化疗敏感的一种策略是降低其抗氧化防御能力并诱导ROS过量产生。关于这一点，尽管抗氧化剂/促氧化剂多酚（如没食子酸（GA））受到一些限制其临床应用的问题的影响，但在几种肿瘤（不包括NB）中，它们显示出促氧化抗癌作用且对健康细胞毒性低。在此，首次对游离GA、两种GA树枝状大分子以及用作GA储存库的树枝状大分子在敏感和耐化疗的NB细胞上进行了测试。以先前发现对敏感NB细胞有活性的剂量给药的树枝状大分子装置，在耐化疗细胞中也诱导了ROS介导的死亡。游离GA在两种细胞群体上均表现出剂量依赖性的ROS介导的细胞毒性。有趣的是，当以对NB细胞无细胞毒性的剂量以树枝状大分子制剂给药时，GA消除了树枝状大分子的任何促氧化活性。不幸的是，由于GA，纳米制剂对NB细胞无活性，但在纳米颗粒中调整大小的GA在低剂量下显示出相当强的抵消树枝状大分子在此处诱导的ROS产生和氧化应激的能力。
