Xiao Hong, Wu Zhuo, Shen Hong, Luo Ai-Lan, Yang Yu-Fei, Li Xiao-Bo, Zhu Dong-Ya
Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China.
Basic Clin Pharmacol Toxicol. 2008 Oct;103(4):342-8. doi: 10.1111/j.1742-7843.2008.00296.x.
P-Glycoprotein-mediated multidrug resistance (MDR) is a major hurdle in cancer therapy. P-Glycoprotein is a 170 KD protein encoded by the MDR1 gene. Over-expression of P-glycoprotein is considered one of the characteristics of the MDR phenotype, thus down-regulation of the MDR1 gene expression will circumvent MDR partly. RNA interference (RNAi) is a process that can result in sequence-specific gene silencing by cleavage target mRNA. Electroporation has been demonstrated to be a promising and efficient method for gene delivery and has been successfully applied in gene therapy. In our study, by using electric pulse to delivery Stealth RNAi into nude mice NCI-H460 tumour xenografts, we successfully inhibited MDR1 both at the mRNA level as determined by reverse transcription-polymerase chain reaction and at the protein level as determined by immunohistochemistry. Furthermore, by administration of navelbine after transfection with Stealth RNAi targeted on the MDR1 gene, its depression to tumour xenografts dramatically improved by nine times. These studies demonstrate that through electrotransfection of Stealth RNAi, P-glycoprotein-mediated MDR can be reversed.
P-糖蛋白介导的多药耐药性（MDR）是癌症治疗中的一个主要障碍。P-糖蛋白是一种由MDR1基因编码的170KD蛋白。P-糖蛋白的过表达被认为是MDR表型的特征之一，因此下调MDR1基因表达将部分规避多药耐药性。RNA干扰（RNAi）是一种可通过切割靶mRNA导致序列特异性基因沉默的过程。电穿孔已被证明是一种有前景且高效的基因递送方法，并已成功应用于基因治疗。在我们的研究中，通过电脉冲将Stealth RNAi递送至裸鼠NCI-H460肿瘤异种移植模型中，我们成功地在mRNA水平（通过逆转录-聚合酶链反应测定）和蛋白质水平（通过免疫组织化学测定）抑制了MDR1。此外，在用靶向MDR1基因的Stealth RNAi转染后给予长春瑞滨，其对肿瘤异种移植模型的抑制作用显著提高了9倍。这些研究表明，通过电转染Stealth RNAi，P-糖蛋白介导的多药耐药性可以被逆转。
