Suppression of mutant androgen receptors by flutamide

Junichiro Ishioka, Shuntaro Hara, John Tod Isaacs, Arihiro Tomura, Kiyohiro Nishikawa, Yukio Kageyama

Research output: Contribution to journalArticle

Abstract

Objectives: To examine the effects of flutamide and hydroxyflutamide on the transactivation of mutant androgen receptors. Methods: Androgen-independent human prostate cancer cell line PC3 was transfected with plasmids expressing wild-type, W741C mutant, T877A mutant or W741C+T877A mutant androgen receptors. The effects of bicalutamide, hydroxyflutamide or flutamide on the basal and dihydrotestosterone-induced transcriptional activities of the wild-type and mutant androgen receptors were evaluated by luciferase assays using a reporter plasmid containing the prostate-specific antigen (PSA) promoter. The effects of the antiandrogens on the transcription and translation of the PSA gene in LNCaP cells expressing a mutant (T877A) androgen receptor were assessed by real-time reverse transcription-polymerase chain reaction and radioimmunoassays. Affinity of the antiandrogens to each androgen receptor construct was evaluated by ligand-binding assay. Results: Flutamide, but not hydroxyflutamide, successfully suppressed the transcription of all of the mutant androgen receptors examined in this study and also showed suppressive effects on PSA secretion by LNCaP cells treated with dihydrotestosterone. These inhibitory effects were probably not the result of competitive inhibition by flutamide given its low affinity to the androgen receptor constructs. Conclusions: Flutamide, with its suppressive effects on mutant androgen receptors, may be an alternative to conventional antiandrogens for hormone refractory prostate cancer.

Original languageEnglish (US)
Pages (from-to)516-521
Number of pages6
JournalInternational Journal of Urology
Volume16
Issue number5
DOIs
StatePublished - May 2009

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Flutamide
Androgen Receptors
Androgen Antagonists
Prostate-Specific Antigen
Dihydrotestosterone
Prostatic Neoplasms
Plasmids
Luciferases
Transcriptional Activation
Androgens
Reverse Transcription
Radioimmunoassay
Hormones
Ligands
Cell Line
Polymerase Chain Reaction

Keywords

  • Androgen
  • Androgen antagonist
  • Neoplasm
  • Prostate
  • Receptor

ASJC Scopus subject areas

  • Urology

Cite this

Suppression of mutant androgen receptors by flutamide. / Ishioka, Junichiro; Hara, Shuntaro; Isaacs, John Tod; Tomura, Arihiro; Nishikawa, Kiyohiro; Kageyama, Yukio.

In: International Journal of Urology, Vol. 16, No. 5, 05.2009, p. 516-521.

Research output: Contribution to journalArticle

Ishioka, J, Hara, S, Isaacs, JT, Tomura, A, Nishikawa, K & Kageyama, Y 2009, 'Suppression of mutant androgen receptors by flutamide', International Journal of Urology, vol. 16, no. 5, pp. 516-521. https://doi.org/10.1111/j.1442-2042.2009.02284.x
Ishioka, Junichiro ; Hara, Shuntaro ; Isaacs, John Tod ; Tomura, Arihiro ; Nishikawa, Kiyohiro ; Kageyama, Yukio. / Suppression of mutant androgen receptors by flutamide. In: International Journal of Urology. 2009 ; Vol. 16, No. 5. pp. 516-521.
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