[In vitro effects of a novel class of nitric oxide donating compounds on isolated human urinary bladder].
作者: G T Kedia ; E Neumayer ; F Scheller ; M A Kuczyk ; S Uckert
Nitric oxide (NO) has been identified an important neurotransmitter involved in the control of the human urinary tract. It has been suggested that NO is one of the factors keeping the bladder relaxed during the filling phase. This function might be mediated by the NO-induced elevation of intracellular cyclic GMP. Prostaglandins (PG) are known to exert contractile effects on the bladder smooth musculature, especially in pathological conditions. The aim of the present study was to examine the effects of a new class of NO donor drugs, combining both anti-phlogistic and NO-donating activity (NCX 2111 and HCT 1026), on the contraction induced by PG or electrical field stimulation (EFS) of isolated human detrusor. Effects were compared to those of sodium nitroprusside (SNP), forskolin, tolterodine, and oxybutynin. Using the organ bath technique, drug effects on the contraction induced by PG ((F2 alpha)) or EFS of isolated human detrusor smooth muscle were investigated. Detrusor strips were also exposed to increasing concentrations of the compounds (0.1 microM - 10 microM) and the accumulation of cyclic GMP and cyclic AMP was determined by means of radioimmunoassays. The tension induced by PG was dose-dependently reversed by the drugs. The rank order of efficacy was: forskolin > SNP > NCX 2111 > HCT 1026. R(max) values ranged from 57% (forskolin) to 24% (HCT 1026). Compounds also dose-dependently reduced the amplitudes of contraction induced by EFS (tolterodine > oxybutynin > NNP = forskolin > HCT 1026 > 2111). The effects of forskolin, HCT 1026, NCX 2111 and SNP were paralleled by an increase in cyclic AMP or cyclic GMP. Our results provide evidence that the NO-cGMP pathway is not of utmost significance in the control of human detrusor smooth muscle. In vitro, the combination of NO-donating with anti-phlogistic activity does not seem to be of functional advantage with regard to the facilitation of detrusor relaxation.
2004-07-01·The Journal of urology1区 · 医学
Nitric oxide donating nonsteroidal anti-inflammatory drugs induce apoptosis in human prostate cancer cell systems and human prostatic stroma via caspase-3.
1区 · 医学
作者: Justine Sarah Royle ; James A Ross ; Ian Ansell ; Prasad Bollina ; David N Tulloch ; Fouad K Habib
New nitric oxide (NO) donating nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized to counteract the side effects of conventional NSAIDs. Mounting evidence suggests that NSAIDs may have a possible chemopreventative/therapeutic role in prostate cancer. NO is a powerful biological messenger with multiple cellular effects. We established the effects of 2 of these new drugs in prostate cell systems.
MATERIALS AND METHODS:
We studied the effects of NO-ibuprofen (NCX 2111) and NO-aspirin (NCX 4060) on hormone sensitive (LNCap) and insensitive (PC3) prostate cancer epithelial cell lines as well as primary cultures of prostatic stroma. Proliferation was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazalium bromide) assay to examine proliferation. Subsequently flow cytometry, cell cycle analysis and TUNEL staining were used to look for apoptosis. Caspase-3 expression was also examined in treated cell types.
NCX 2111 and NCX 4060 were found to be potent inhibitors of proliferation in a dose dependent fashion. The 2 drugs induced apoptosis, as seen by flow cytometry, cell cycle analysis and TUNEL staining, at doses between 10 and 100 microM. These NO-NSAIDs increased caspase-3 expression. NCX 4060 was more effective at lower concentrations (10 microM) but each compound was much more potent than conventional ibuprofen and aspirin at inducing apoptosis and inhibiting proliferation.
NO-NSAIDs are potent antiproliferative pro-apoptotic compounds in prostate cell systems. This pro-apoptotic effect is mediated via caspase-3 and it is independent of the type of prostate cell used. These findings have ramifications for the use of these new drugs in prostate cancer chemoprevention or treatment.