Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity

Prostate. 2010 May 15;70(7):745-54. doi: 10.1002/pros.21107.


Background: Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status. However, the mechanism of bicalutamide resistance remains unclear because few cell models have been generated.

Methods: We generated a bicalutamide-resistant subline, LNCaP-BC2, from LNCaP after prolonged treatment with bicalutamide. Androgen and/or bicalutamide responsiveness for proliferation and prostate-specific antigen (PSA) secretion were examined in vitro and in vivo. Testosterone and dihydrotestosterone (DHT) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry. Androgen receptor (AR) gene mutation and amplification and AR and pAR(210) expression were determined.

Results: LNCaP-BC2 did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP. LNCaP-BC2 grew in castrated male mice, and the DHT level in grafted LNCaP-BC2 tumors was 7.7-fold lower than in LNCaP tumors. Bicalutamide stimulated LNCaP-BC2 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP-BC2 was weaker than that of LNCaP in vivo. Additional AR mutation and AR gene amplification were not detected in LNCaP-BC2, but AR and pAR(210) expression and PSA secretion in LNCaP-BC2 were higher than in LNCaP.

Conclusions: Bicalutamide-resistant LNCaP-BC2 exhibited AR overexpression and hypersensitivity to low levels of androgen. Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion. In addition, pAR(210) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP-BC2.

MeSH terms

  • Androgen Antagonists / administration & dosage
  • Anilides / administration & dosage*
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Dihydrotestosterone / analysis
  • Enzyme-Linked Immunosorbent Assay
  • Male
  • Mice
  • Nitriles / administration & dosage*
  • Prostate / cytology
  • Prostate / drug effects*
  • Prostate / metabolism
  • Prostate-Specific Antigen / analysis
  • Receptors, Androgen / metabolism*
  • Testosterone / analysis
  • Time Factors
  • Tosyl Compounds / administration & dosage*


  • Androgen Antagonists
  • Anilides
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • Dihydrotestosterone
  • Testosterone
  • bicalutamide
  • Prostate-Specific Antigen