Reversal of MDR1 gene-dependent multidrug resistance using low concentration of endonuclease-prepared small interference RNA.
Multidrug resistance following initial chemotherapy is commonly associated with MDR1 gene encoding for P-glycoprotein (P-gp). RNA interference of MDR1 gene expression was used as a strategy to reverse MDR1-mediated multidrug resistance phenotypes. Here we report that endonuclease-prepared small interfering RNA (esiRNA) at concentrations as low as 10 ng/ml (about 0.7 nM) can decrease MDR1 expression and increase chemosensitivity in the Adriamycin-induced resistant MCF-7/R cells. When MCF-7/R cells were transiently transfected with esiRNA of MDR1 (esiMDR1), the MDR1 mRNA was reduced by about 50%, drug accumulation increased by about 30%, and the IC50 for daunorubicin was reduced from 4.5 to 1.2 microM. These results provide evidence that esiRNA of MDR1 could be an alternative to P-gp inhibitors with the advantage of avoiding non-specific suppression with a lower effective dosage than using a single siRNA duplex, offering a potential therapeutic application of siRNA.
Li
Lin
L
Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai 200433, China.
Xu
Jianfeng
J
Min
Taishan
T
Huang
Weida
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010957:Plasmids / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism / Q000493:pharmacokinetics; D043244:Ribonuclease III / Q000378:metabolism; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D020112:Rhodamine 123; D043244:Ribonuclease III; D003630:Daunorubicin