Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells

Cancer Res. 2003 Apr 1;63(7):1515-9.

Abstract

Overexpression of P-glycoprotein (P-gp), the MDR1 gene product, confers multidrug resistance (MDR) to cancer cells. Clinically, MDR is one of the major causes for chemotherapeutic treatment failure in cancer patients. To explore a new approach to circumventing MDR, we adopted RNA interference to target MDR1 gene expression. RNA interference is a conserved biological response to double-stranded RNA, which results in sequence-specific gene silencing [G. J. Hannon, Nature (Lond.), 418: 244-251, 2002]. We report that introduction of an MDR1-targeted small interfering RNA duplex into drug-resistant cancer cells markedly inhibited the expression of MDR1 mRNA and P-gp, as determined by reverse transcription-PCR and Western blot. Inhibition of P-gp expression by small interfering RNA enhanced the intracellular accumulation of and selectively restored sensitivity to drugs transported by P-gp. These studies indicate that RNA interference can modulate MDR in preclinical models.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / genetics*
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, MDR / genetics*
  • Humans
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / pharmacology
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics*
  • Transfection
  • Tumor Cells, Cultured
  • Vinblastine / pharmacokinetics
  • Vinblastine / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • RNA, Small Interfering
  • Vinblastine
  • Doxorubicin
  • Paclitaxel