RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine

Oncogene. 2004 Feb 26;23(8):1539-48. doi: 10.1038/sj.onc.1207272.

Abstract

Ribonucleotide reductase is emerging as an important determinant of gemcitabine chemoresistance in human cancers. Activity of this enzyme, which catalyses conversion of ribonucleotide 5'-diphosphates to their 2'-deoxynucleotides, is modulated by levels of its M2 subunit (RRM2). Here we show that RRM2 overexpression is associated with gemcitabine chemoresistance in pancreatic adenocarcinoma cells, and that suppression of RRM2 expression using RNA interference mediated by small interfering RNA (siRNA) enhances gemcitabine-induced cytotoxicity in vitro. We demonstrate the ability of systemically administered RRM2 siRNA to suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma. Synergism between RRM2 siRNA and gemcitabine results in markedly suppressed tumor growth, increased tumor apoptosis and inhibition of metastasis. Our findings confirm the importance of RRM2 in pancreatic adenocarcinoma gemcitabine chemoresistance. This is the first demonstration that systemic delivery of siRNA-based therapy can enhance the efficacy of an anticancer nucleoside analog.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use*
  • Drug Synergism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • RNA, Small Interfering / metabolism
  • Ribonucleoside Diphosphate Reductase / antagonists & inhibitors*
  • Ribonucleoside Diphosphate Reductase / genetics
  • Ribonucleoside Diphosphate Reductase / metabolism
  • Time Factors
  • Transplantation, Heterologous

Substances

  • Antimetabolites, Antineoplastic
  • RNA, Small Interfering
  • Deoxycytidine
  • gemcitabine
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase