Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR1.
Overexpression of P-glycoprotein, encoded by the MDR1 gene, confers multidrug resistance (MDR) on cancer cells and is a frequent impediment to successful chemotherapy. Recent developments in the use of small interfering RNAs to inhibit specific protein expression have highlighted their potential use as therapeutic agents. We have expressed two different short hairpin RNAs from stably integrated plasmids in doxorubicin-resistant K562 leukaemic cells. The MDR1-targeted RNA interference (RNAi) resulted in decreased MDR1 mRNA, abolished P-glycoprotein expression, and completely reversed the MDR phenotype to that of the drug-sensitive K562 parental line. This study demonstrates that MDR, which is solely due to overexpression of P-glycoprotein, can be reversed by RNAi. These target sequences can in the future be integrated into gene therapy vectors with potential clinical application.
Yagüe
E
E
Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London, UK.
Higgins
C F
CF
Raguz
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation; D018390:Gene Targeting; D019450:Genes, MDR; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004317:Doxorubicin