Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture

M. Fathy El Etreby, Yayun Liang, Ronald W. Lewis

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Published data indicate that antiprogestins and antiestrogens could inhibit prostate cancer cell growth in vitro and in vivo. The main objective of the present studies was to explore the role of bcl2 and TGFβ1 for induction of apoptosis in LNCaP prostate cancer cells growing in culture as a treatment response to the antiprogestin, mifepristone, and the antiestrogen, 4-hydroxytamoxifen. METHODS. In vitro cell viability (cytotoxicity), DNA fragmentation, and changes in the expression of bcl2 and TGFβ1 proteins were assessed using the sulforhodamine B protein dye-binding assay, specific ELISA, and competitive inhibition assays. RESULTS. Both steroid antagonists induced a significant time- and dose-dependent cell growth inhibition (cytotoxicity). This inhibition of viable cells was associated with a significant increase in DNA fragmentation (apoptosis), downregulation of bcl2, and induction of TGFβ1 protein. Abrogation of the mifepristone- and 4-hydroxytamoxifen-induced cytotoxicity by TGFβ1- neutralizing antibody and by the addition of mannose-6-phosphate confirmed the correlation between induction of active TGFβ1 and subsequent prostate cancer cell death. The effect of mifepristone was not significantly reduced or prevented by occupying the progesterone or glucocorticoid receptors by their corresponding high-affinity native ligands. On the contrary, the effect of a combination of mifepristone with progesterone or hydrocortisone on the increase in DNA fragmentation, bcl2 downregulation, and induction of TGFβ1 protein was additive and significantly different (P < 0.05) from the effect of mifepristone monotherapy. CONCLUSIONS. Our data suggest that mifepristone and tamoxifen are effective inducers of apoptosis and may represent nonandrogen-ablation, novel therapeutic approaches to overcome a potential intrinsic apoptosis resistance of androgen-independent prostate cancer cells. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)31-42
Number of pages12
JournalProstate
Volume43
Issue number1
DOIs
StatePublished - Jan 1 2000

Keywords

  • Antiestrogens
  • Antiprogestins
  • Cell growth inhibition
  • TGFβ
  • bcl

ASJC Scopus subject areas

  • Oncology
  • Urology

Fingerprint Dive into the research topics of 'Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture'. Together they form a unique fingerprint.

Cite this