Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction

Br J Cancer. 2003 May 19;88(10):1615-21. doi: 10.1038/sj.bjc.6600961.


Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Adrenergic alpha-Antagonists / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / pharmacology
  • Doxazosin / pharmacology*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Prostatic Neoplasms / pathology*
  • Protein Serine-Threonine Kinases / pharmacology
  • Quinazolines / pharmacology*
  • RNA, Messenger / biosynthesis
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Receptors, Adrenergic, alpha-1 / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transforming Growth Factor beta / pharmacology*


  • Adrenergic alpha-Antagonists
  • Quinazolines
  • RNA, Messenger
  • Receptors, Adrenergic, alpha-1
  • Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Doxazosin