Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka 576104, India.
Exp Mol Pathol. 2013 Feb;94(1):137-47. doi: 10.1016/j.yexmp.2012.10.007. Epub 2012 Oct 10.
With the advent of advanced tools in molecular biology, understanding on cancer etiology has improved. siRNA can be considered as an effective tool in cancer therapy through silencing overexpressed genes responsible for cell proliferation or preventing apoptosis. However, some contentious issues such as stability and delivery of siRNA are to be resolved. Bcl-2, an anti-apoptotic gene, is overexpressed in a wide variety of cancers and responsible for drug resistance tumors. In our earlier studies, we developed a nanoformulation of siRNA targeting the Bcl-2 and achieved successful delivery in vitro and in vivo. To extend the scope of the study further, in the present work, we studied the role of nanoformulation of siRNA as adjuvant in chemotherapy with cisplatin. Dose dependant nephrotoxicity is a serious concern apart from other adverse effects of cisplatin. The IC(50) value for cisplatin was decreased from 9.83 μmol/l to 7.43 μmol/l in HeLa cells and from 8.54 μmol/l to 6.68 μmol/l in HEp-2 cells, when it was given with siRNA nanoformulation. Cisplatin at the dose of 1.7 mg/kg in combination with siRNA nanoformulation was effective in improving the lifespan of tumor bearing mice with significant decrease in nephrotoxicity.
随着分子生物学先进工具的出现，人们对癌症病因的理解有所提高。siRNA 可以被视为一种通过沉默负责细胞增殖的过表达基因或阻止细胞凋亡来治疗癌症的有效工具。然而，一些有争议的问题，如 siRNA 的稳定性和传递，仍有待解决。Bcl-2 是一种抗凋亡基因，在多种癌症中过表达，导致肿瘤耐药。在我们早期的研究中，我们开发了一种针对 Bcl-2 的 siRNA 纳米制剂，并在体外和体内实现了成功传递。为了进一步扩展研究范围，在本研究中，我们研究了 siRNA 纳米制剂作为顺铂化疗辅助剂的作用。除了顺铂的其他不良反应外，剂量依赖性肾毒性是一个严重的问题。当与 siRNA 纳米制剂一起使用时，顺铂在 HeLa 细胞中的 IC50 值从 9.83 μmol/L 降低到 7.43 μmol/L，在 HEp-2 细胞中的 IC50 值从 8.54 μmol/L 降低到 6.68 μmol/L。当顺铂以 1.7 mg/kg 的剂量与 siRNA 纳米制剂联合使用时，可有效延长荷瘤小鼠的寿命，并显著降低肾毒性。
