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Relative cytotoxic potencies and cell death mechanisms of α1-adrenoceptor antagonists in prostate cancer cell lines
Prostate
  • Amanda Forbes, Bond University
  • Shailendra Anoopkumar-Dukie, Griffith University
  • Russ Chess-Williams, Bond University
  • Catherine M. McDermott, Bond University
Date of this Version
2-19-2016
Document Type
Journal Article
Publication Details

Citation only

Forbes, A., Anoopkumar-Dukie, S., Chess-Williams, R., & McDermott, C. (2016, in press). Relative cytotoxic potencies and cell death mechanisms of α1-adrenoceptor antagonists in prostate cancer cell lines. Prostate.

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© Copyright, Wiley Periodicals, 2016

Disciplines
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 (0.01-100μM) and cell survival assessed after 24-72hr. 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 (30μM) 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.

Citation Information
Amanda Forbes, Shailendra Anoopkumar-Dukie, Russ Chess-Williams and Catherine M. McDermott. "Relative cytotoxic potencies and cell death mechanisms of α1-adrenoceptor antagonists in prostate cancer cell lines" Prostate (2016) ISSN: 0270-4137
Available at: http://works.bepress.com/catherine_mcdermott/18/