cGMP-independent anti-tumour actions of the inhibitor of soluble guanylyl cyclase, ODQ, in prostate cancer cell lines

G. Haramis, Z. Zhou, A. Pyriochou, M. Koutsilieris, C. Roussos, Andreas Papapetropoulos

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background and purpose: Soluble guanylyl cyclase (sGC) is a receptor for nitric oxide that generates cGMP. This second messenger molecule has established roles in cellular physiology; however, less is known about its effects in tumour cells. Experimental approach: The effects of 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin- 1-one (NS2028), both selective sGC inhibitors on proliferation, death and migration were determined in prostate cancer cell lines. Key results: Western blot analysis confirmed the presence of α1 and β1 subunits of sGC in LNCaP and PC-3 cells. Sodium nitroprusside (SNP) increased cGMP accumulation in LNCaP and PC-3, but not DU-145 cells. SNP-stimulated cGMP production in LNCaP cells was dose-dependently reduced by ODQ, with more than 90% inhibition being observed at 0.1 μM. ODQ activated caspase-3 in all three cell lines, but not in normal prostate epithelial cells, at concentrations over 10 μM. High concentrations of ODQ also promoted DNA fragmentation and nucleosome accumulation in the cytosol of LNCaP cells. Interestingly, the chemically related inhibitor, NS2028 was without effect on caspase-3. In addition, ODQ inhibited LNCaP, Du145 and PC-3 cell growth. Finally, although fibroblast growth factor-2 did not enhance cGMP levels in LNCaP cells, its ability to stimulate LNCaP motility was abolished by ODQ. Conclusions and implications: These observations taken together suggest that the action of ODQ in LNCaP cells did not reflect sGC inhibition. We conclude that ODQ promotes cell death and inhibits growth and migration of prostate cancer cells and that these actions are independent of its effects on GMP levels.

Original languageEnglish (US)
Pages (from-to)804-813
Number of pages10
JournalBritish Journal of Pharmacology
Volume155
Issue number6
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Cell Line
Neoplasms
Nitroprusside
Caspase 3
Soluble Guanylyl Cyclase
Nucleosomes
Second Messenger Systems
Fibroblast Growth Factor 2
DNA Fragmentation
Growth
Cytosol
Prostate
Cell Death
Western Blotting
Epithelial Cells
NS 2028

Keywords

  • Apoptosis
  • Cell proliferation
  • Nitric oxide
  • ODQ
  • Prostate cancer
  • sGC

ASJC Scopus subject areas

  • Pharmacology

Cite this

cGMP-independent anti-tumour actions of the inhibitor of soluble guanylyl cyclase, ODQ, in prostate cancer cell lines. / Haramis, G.; Zhou, Z.; Pyriochou, A.; Koutsilieris, M.; Roussos, C.; Papapetropoulos, Andreas.

In: British Journal of Pharmacology, Vol. 155, No. 6, 01.11.2008, p. 804-813.

Research output: Contribution to journalArticle

Haramis, G. ; Zhou, Z. ; Pyriochou, A. ; Koutsilieris, M. ; Roussos, C. ; Papapetropoulos, Andreas. / cGMP-independent anti-tumour actions of the inhibitor of soluble guanylyl cyclase, ODQ, in prostate cancer cell lines. In: British Journal of Pharmacology. 2008 ; Vol. 155, No. 6. pp. 804-813.
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AU - Koutsilieris, M.

AU - Roussos, C.

AU - Papapetropoulos, Andreas

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AB - Background and purpose: Soluble guanylyl cyclase (sGC) is a receptor for nitric oxide that generates cGMP. This second messenger molecule has established roles in cellular physiology; however, less is known about its effects in tumour cells. Experimental approach: The effects of 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin- 1-one (NS2028), both selective sGC inhibitors on proliferation, death and migration were determined in prostate cancer cell lines. Key results: Western blot analysis confirmed the presence of α1 and β1 subunits of sGC in LNCaP and PC-3 cells. Sodium nitroprusside (SNP) increased cGMP accumulation in LNCaP and PC-3, but not DU-145 cells. SNP-stimulated cGMP production in LNCaP cells was dose-dependently reduced by ODQ, with more than 90% inhibition being observed at 0.1 μM. ODQ activated caspase-3 in all three cell lines, but not in normal prostate epithelial cells, at concentrations over 10 μM. High concentrations of ODQ also promoted DNA fragmentation and nucleosome accumulation in the cytosol of LNCaP cells. Interestingly, the chemically related inhibitor, NS2028 was without effect on caspase-3. In addition, ODQ inhibited LNCaP, Du145 and PC-3 cell growth. Finally, although fibroblast growth factor-2 did not enhance cGMP levels in LNCaP cells, its ability to stimulate LNCaP motility was abolished by ODQ. Conclusions and implications: These observations taken together suggest that the action of ODQ in LNCaP cells did not reflect sGC inhibition. We conclude that ODQ promotes cell death and inhibits growth and migration of prostate cancer cells and that these actions are independent of its effects on GMP levels.

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