Induction of Apoptosis by Survivin Silencing through siRNA Delivery in a Human Breast Cancer Cell Line
Induction of Apoptosis by Survivin Silencing through siRNA Delivery in a Human Breast Cancer Cell Line
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DOI：
10.1021/mp200176v
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发表时间：
2011-09-01
影响因子：
4.9
通讯作者：
Uludag, Hasan
中科院分区：
文献类型：
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作者：
Aliabadi, Hamidreza Montazeri;Landry, Breanne;Uludag, Hasan
抗凋亡基因的转录后沉默是癌症治疗的一种有前途的策略，但由于阴离子siRNA不能穿过细胞膜，因此递送针对此类靶标的短干扰RNA（siRNA）分子具有挑战性。小分子量、无毒的聚乙烯亚胺（PEI）上的脂质取代已经被研究为有效siRNA递送的有前景的方法。在这项研究中，我们报告的能力，低分子量，脂质取代PEI提供siRNA抗凋亡蛋白生存素。在MDA-MB-231人乳腺癌细胞中评价脂质取代的PEI文库的毒性以及它们的siRNA递送和存活素沉默效率。由于脂质取代，观察到siRNA的细胞递送显著增加。最显着的下调生存素建立辛酸取代的聚合物，这导致了显着水平的细胞凋亡诱导和细胞活力的损失。在抗癌药物治疗前下调生存素可使几种药物的IC（50）降低50- 120倍。我们的实验表明，通过用疏水修饰的PEI递送siRNA，有效下调存活素，存活素是一种在肿瘤细胞中上调的细胞保护蛋白。这项研究介绍了一种有前途的安全有效的siRNA递送系统，将适合在临床前动物模型中进行进一步研究。
Post-transcriptional silencing of antiapoptotic genes is a promising strategy for cancer therapy, but delivering short interfering RNA (siRNA) molecules against such targets is challenging due to inability of anionic siRNA to cross cellular membranes. Lipid substitution on small molecular weight, nontoxic polyethylenimine (PEI) has been investigated as a promising approach for effective siRNA delivery. In this study, we report on the ability of low molecular weight, lipid-substituted PEI to deliver siRNA against the antiapoptotic protein survivin. Toxicity of a library of lipid-substituted PEIs, as well as their siRNA delivery and survivin silencing efficiency, was evaluated in MDA-MB-231 human breast cancer cells. A significant increase in cellular delivery of siRNA was observed as a result of lipid substitution. Most significant downregulation of survivin was established by caprylic acid-substituted polymers, which resulted in significant levels of apoptosis induction and resultant loss of cell viability. Survivin downregulation prior to anticancer drug treatment decreased the IC(50) of several drugs by 50- to 120-fold. Our experiments indicated an effective downregulation of survivin, a cell protective protein upregulated in tumor cells, by delivering siRNA with hydrophobically modified PEI. This study introduces a promising delivery system for safe and effective siRNA delivery that will be suitable for further investigation in preclinical animal models.