Hydroxyurea decreases gemcitabine resistance in pancreatic carcinoma cells with highly expressed ribonucleotide reductase

Pancreas. 2012 Jan;41(1):107-13. doi: 10.1097/MPA.0b013e318224b5fb.

Abstract

Objectives: This study aimed to determine whether the treatment of pancreatic carcinoma can be defined on the basis of the expression of genes involved in gemcitabine metabolism and whether combination treatment is more effective than conventional treatment.

Methods: Four pancreatic carcinoma cell lines (Panc-1, MIAPaCa-2, BxPC-3, and Capan-2) were used to determine the patterns of gemcitabine-metabolizing genes and mesenchymal marker gene expressions using quantitative real-time polymerase chain reaction. Chemosensitivity and cell proliferation were measured using colorimetric assay. Gemcitabine was combined with hydroxyurea or small interfering RNA targeting ribonucleotide reductase to assess changes in chemoresistance.

Results: Panc-1 and MIAPaCa-2 cell lines were profoundly chemoresistant and expressed genes corresponding to cells with distinct mesenchymal phenotypes. In addition, Panc-1 highly expressed ribonucleotide reductase and showed a 4-fold increase in gemcitabine sensitivity after treatment with hydroxyurea.

Conclusions: Combination treatment tailored to cells with highly expressed ribonucleotide reductase was more effective than treatment with gemcitabine alone. Moreover, phenotype and gemcitabine metabolism may independently confer chemoresistance.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Antigens, CD
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hydroxyurea / pharmacology*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleotide Reductases / antagonists & inhibitors
  • Ribonucleotide Reductases / genetics*
  • Ribonucleotide Reductases / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Vimentin / genetics
  • Vimentin / metabolism
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • ABCB9 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antigens, CD
  • Antineoplastic Agents
  • CDH1 protein, human
  • Cadherins
  • Homeodomain Proteins
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Vimentin
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Deoxycytidine
  • gemcitabine
  • Ribonucleotide Reductases
  • Hydroxyurea
  • multidrug resistance-associated protein 1