title: Relative cytotoxic potencies and cell death mechanisms of α1 -adrenoceptor antagonists in prostate cancer cell lines.
abstract: BACKGROUND
  Some α1 -adrenoceptor antagonists possess anti-cancer actions that are independent of α1 -adrenoceptors and the aim of these studies was to assess the relative cytotoxic potencies of α1 -adrenoceptor antagonists and the mechanisms involved in these actions.
  
  
  METHODS
  PC-3 and LNCap human prostate cancer cells were exposed to α1 -adrenoceptor antagonists (0.01-100 μM) and cell survival assessed after 24-72 hr. The levels of apoptosis, autophagy and stress related proteins were also determined.
  
  
  RESULTS
  The relative cytotoxic potency order was prazosin = doxazosin > terazosin = silodosin = alfuzosin > tamsulosin on both cell types, but LNCaP cells were significantly more sensitive to these effects than PC-3 cells. Prazosin and doxazosin increased levels of apoptotsis and autophagy in both cell lines, and activated EphA2 receptors in PC-3 cells. Autophagy contributed to survival of LNCaP, but promoted cell death in PC-3 cells. Treatment with prazosin (30 μM) altered the expression of several cell stress-related proteins: elevating phospho-p38α and reducing S6 kinase in both cell lines. Surprisingly some proteins were differentially affected in the two prostate cancer cell lines: Akt and p27 increasing and HIF-1α decreasing in LNCap cells but not PC-3, while ADAMTS1 was increased in PC-3 cells only.
  
  
  CONCLUSIONS
  Prazosin and doxazosin demonstrated cytotoxic actions on both castration-resistant PC-3 and androgen-sensitive LNCap prostate cancer cells. The mechanisms involved included changes in a number of proliferation and apoptosis regulatory proteins. The role of autophagy depended on the cell type, but contributed to cell death in PC3 cells.
authors.affiliation: Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Queensland, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Forbes
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Queensland Australia School of Pharmacy, Griffith University, Queensland, Australia.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Anoopkumar-Dukie
authors.affiliation: Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Queensland, Australia.
authors.forename: Russ
authors.initials: R
authors.lastname: Chess-Williams
authors.affiliation: Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Queensland, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: McDermott
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077409:Tamsulosin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011799:Quinazolines; D013449:Sulfonamides; C041226:Terazosin; C047638:alfuzosin; C095285:silodosin; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D000077409:Tamsulosin; D017292:Doxazosin; D011224:Prazosin
keywords: LNCaP; PC-3; apoptosis; autophagy; α1-adrenoceptor antagonists