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Mifepristone-induced secretion of transforming growth factor beta1-induced apoptosis in prostate cancer cells

Yayun Liang1, Manal A Eid, Fathy El Etreby

  • 1Medical College of Georgia, Section of Urology, Augusta, GA 30912-4050, USA.

International Journal of Oncology
|November 14, 2002
PubMed

Insights

Mifepristone and Tamoxifen induce apoptosis in prostate cancer cells via transforming growth factor beta1 (TGFbeta1). Mifepristone demonstrated greater efficacy, with TGFbeta1 mediation confirmed by blocking its function, leading to apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Prostate cancer therapy requires inducing apoptosis regardless of androgen response.
  • Mifepristone and Tamoxifen are investigated for their potential in prostate cancer treatment.
  • Preliminary data suggested these drugs induce apoptosis.

Purpose of the Study:

  • To investigate the mechanism of apoptosis induction by Mifepristone and Tamoxifen in prostate cancer cells.
  • To evaluate the efficacy of Mifepristone and Tamoxifen in vivo using xenografts.
  • To determine the role of transforming growth factor beta1 (TGFbeta1) in drug-induced apoptosis.

Main Methods:

  • Prostate cancer cells (LNCaP-C4) were treated with Mifepristone and/or Tamoxifen.
  • Cell viability was assessed using Sulforhodamine B (SRB) assay; DNA fragmentation was measured by ELISA.
  • TGFbeta1 secretion was quantified, and its role was confirmed by antibody neutralization or M6P inhibition.
  • Apoptosis was further analyzed by immunoblotting for cytochrome c and measuring caspase-3 activity.

Main Results:

  • Both Mifepristone and Tamoxifen induced apoptosis in LNCaP-C4 cells, with Mifepristone showing higher effectiveness.
  • In vivo xenograft studies corroborated the in vitro findings.
  • Neutralizing TGFbeta1 or blocking its activation abrogated the apoptotic effects, confirming TGFbeta1's crucial role.
  • Drug treatment led to cytochrome c release and increased caspase-3 activity, indicating apoptosis induction mediated by TGFbeta1.

Conclusions:

  • Mifepristone and Tamoxifen effectively induce apoptosis in prostate cancer cells through a mechanism involving TGFbeta1 secretion.
  • Mifepristone appears more potent than Tamoxifen in this context.
  • Combination therapy with Tamoxifen did not offer a significant advantage over Mifepristone alone.

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