NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway.

Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.

Intravesical prostatic protrusion is better than prostate volume in predicting the outcome of trial without catheter in white men presenting with acute urinary retention: a prospective clinical study.

PURPOSE: Trial without catheter after a short course of an alpha-blocker in men presenting with acute urinary retention is successful in up to 50% of cases. The ability to better predict outcome could avoid a trial without catheter for some men. Intravesical prostatic protrusion and not prostate volume has been shown to predict trial without catheter outcome in an Asian cohort. We investigated the relationship between the outcome of trial without catheter and prostate volume and intravesical prostatic protrusion in white men given alpha-blockers before a trial without catheter. MATERIALS AND METHODS: Consecutive men 50 years old or older presenting with acute urinary retention were prospectively recruited based on strict selection criteria. At presentation factors thought to precipitate acute urinary retention were treated, alpha-blocker therapy started and the patient brought back for a trial without catheter after 2 weeks. Prostate volume and intravesical prostatic protrusion were measured by standard transrectal ultrasonography. RESULTS: Of 121 men presenting with acute urinary retention 57 fulfilled the study selection criteria. Mean (+/- SD) age, prostate volume and intravesical prostatic protrusion of recruited men were 70 +/- 9.2 years, 69.7 +/- 36.3 ml and 12.8 +/- 10.1 mm, respectively. A total of 25 men (43.9%) had a successful trial without catheter. Mean intravesical prostatic protrusion was significantly smaller in those who had a successful trial without catheter (7.2 vs 16.5 mm, 95% CI 4.5-14, p <0.001). With intravesical prostatic protrusion correlating well with prostate volume (r = 0.588), mean prostate volume was also smaller in men with a successful trial without catheter, albeit with a smaller effect size. Men with an intravesical prostatic protrusion of 10 mm or less, compared to those with a larger intravesical prostatic protrusion, were 6 times more likely to have a successful trial without catheter. CONCLUSIONS: In this cohort presenting with acute urinary retention related to benign prostatic hyperplasia and receiving alpha-blockers before a trial without catheter, intravesical prostatic protrusion appears to strongly predict the outcome of a trial without catheter. A trial without catheter is more likely to fail in patients with intravesical prostatic protrusion larger than 10 mm.