Reversal of MDR1 gene-dependent multidrug resistance using low concentration of endonuclease-prepared small interference RNA

Eur J Pharmacol. 2006 Apr 24;536(1-2):93-7. doi: 10.1016/j.ejphar.2006.02.050. Epub 2006 Mar 3.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • CHO Cells
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cricetinae
  • Cricetulus
  • Daunorubicin / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Plasmids / genetics
  • RNA Interference*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Rhodamine 123 / metabolism
  • Rhodamine 123 / pharmacokinetics
  • Ribonuclease III / metabolism
  • Transfection

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Rhodamine 123
  • Ribonuclease III
  • Daunorubicin