Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine

BJU Int. 2004 Jun;93(9):1333-8. doi: 10.1111/j.1464-410X.2004.04847.x.

Abstract

Objective: To assess the involvement of the multidrug resistance-associated protein 1 (MRP1) and the glutathione pathway in the multidrug resistant (MDR) phenotype of prostate cancer in vitro.

Materials and methods: Chemoselection of human prostate cancer cell lines PC3 and DU145 with etoposide resulted in the resistant cell lines PC3-R and DU-R. Resistance against etoposide, doxorubicin and vincristine, and its reversal with leukotriene D4 antagonists MK-571 and zafirlukast, and buthionine sulfoximine (BSO), was assessed using tetrazolium-dye viability assays. Western blot analysis of MRP1 expression and glutathione content were measured, and MRP1 function assessed in fluorescence assays.

Results: MRP1 was increased in the MDR models; the glutathione content was significantly higher in PC3-R but there was no increase in glutathione in DU-R. Adding non-toxic doses of MK-571, zafirlukast or BSO significantly increased the sensitivity of the MDR models to cytotoxic drugs. MRP1 function was inhibited with MK-571 in the MDR models.

Conclusion: MRP1 and glutathione mediate MDR in newly developed prostate cancer models.

MeSH terms

  • Blotting, Western
  • Buthionine Sulfoximine / pharmacology*
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Glutathione / physiology*
  • Humans
  • Leukotriene Antagonists / pharmacology*
  • Male
  • Multidrug Resistance-Associated Proteins / physiology*
  • Propionates / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Quinolines / pharmacology

Substances

  • Enzyme Inhibitors
  • Leukotriene Antagonists
  • Multidrug Resistance-Associated Proteins
  • Propionates
  • Quinolines
  • Buthionine Sulfoximine
  • verlukast
  • Glutathione
  • multidrug resistance-associated protein 1