In vivo reversal of P-glycoprotein-mediated multidrug resistance by efficient delivery of stealth RNAi.
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.
Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China. xhnkyy@yahoo.com.cn
Hong
H
Xiao
Zhuo
Z
Wu
Hong
H
Shen
Ai-Lan
AL
Luo
Yu-Fei
YF
Yang
Xiao-Bo
XB
Li
Dong-Ya
DY
Zhu
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018274:Electroporation; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D014747:Vinblastine; D000077235:Vinorelbine