Prostatic diseases are characterized by increased activity of cytokines, growth factors, and cyclooxygenases- (COX-) 1 and 2. Activation of COX-1 and COX-2 results in increased levels of prostaglandins and the induction of angiogenic, antiapoptotic and inflammatory processes. Inhibition of COX enzymes by members of the widely used nonsteroidal anti-inflammatory drug (NSAID) class of drugs decreases prostaglandin production, and exerts a variety of anti-inflammatory, antipyretic, and antinociceptive effects. While numerous in vitro, in vivo, and clinical studies have shown that NSAIDs inhibit the risk and progression of prostatic diseases, the relationship between NSAIDs and such diseases remains controversial. Here we review the literature in this area, critically analyzing the benefits and caveats associated with the use of NSAIDs in the treatment of prostatic diseases.
1. Introduction
The initiation and progression of prostatic diseases involve a variety of factors, including the amplification and mutation of genes encoding the androgen receptor, tumor suppressor genes, oncogenes, growth factors, and cytokines, in addition to other processes such as infection [1–4]. Given the role of inflammation in the development and progression of prostatic disease, it has been suggested that inhibition of inflammation would decrease the risk of prostatic diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the world for their antinociceptive, anti-inflammatory, and antipyretic effects in many diseases, including prostate cancer and prostatic disease. In contrast, several studies have reported that the use of NSAIDs increases the risk of prostatic diseases and the relationship between this class of drugs and prostatic disease remains controversial. Current opinion suggests that NSAID treatment would be beneficial for most prostatic diseases, in particular benign prostatic hyperplasia (BPH) and prostate cancer. In this review, we discuss the relationship between NSAIDs and prostatic diseases.
2. NSAIDs
The primary mechanism of action of NSAIDs is the inhibition of the activity of cyclooxygenase enzymes (COX-1 and COX-2) and a consequent reduction in prostaglandin levels [5]. COX-1 is constitutively expressed in most tissues and has important roles in tissue homeostasis, particularly in the stomach and kidney, as well as in blood clotting. In contrast, expression of COX-2 is induced by cytokines or growth factors [6]. Both enzymes convert arachidonic acid to prostaglandin G2 (Figure 1), which is in turn converted to various mediators of inflammation, including prostaglandin H, prostaglandin E, prostaglandin D, and thromboxane A.
Schematic of the mechanism of action of NSAIDs. NSAID inhibition of cyclooxygenase-1 and/or cyclooxygenase-2 suppresses prostaglandin G2 production, promoting apoptosis and blocking angiogenesis, inflammation, and tumor progression.
NSAIDs are classified into two groups: COX-2 nonselective NSAIDs, which inhibit both COX-2 and COX-1 and COX-2 selective NSAIDs. Since COX-1 inhibition has been associated with severe side effects such as gastrointestinal bleeding and damage to gastric mucosa [7], there has been an emphasis on the development of COX-2 selective NSAIDs. COX-2 selective NSAIDs have been shown to inhibit inflammation without damaging the gastric mucosa [8], although some have been linked with cardiovascular toxicity [9].
Given the myriad adverse side effects of classical NSAIDs, increasing attention is being focused on nitric oxide-donating NSAIDs (NO-NSAIDs), which are associated with fewer side effects [10]. NO released from NO-NSAIDs inhibits gastrointestinal bleeding and damage to the gastric mucosa by increasing blood flow and mucus secretion. Moreover, NO-NSAIDs have been shown to be more effective inhibitors of cancer cell growth than classical NSAIDs [10]. Collectively these data suggest that NSAIDs have potential as a novel class of drugs for the prevention of prostatic diseases and prostate cancer.
3. Prostatitis
According to the NIH consensus classification of prostatitis syndromes includes 4 categories. These four categories include (1) acute bacterial prostatitis, (2) chronic bacterial prostatitis, (3) chronic prostatitis/CPPS consisting of A: inflammatory and B: noninflammatory, and (4) asymptomatic inflammatory prostatitis [11]. While antibacterial drugs are effective in the treatment of acute bacterial prostatitis, they are less effective in the treatment of the other types of prostatitis. As a consequence, therapy for chronic prostatitis is primarily aimed at managing its symptoms. COX-2 selective NSAIDs have been shown to abrogate or partially relieve dysuric symptoms in 66% and 17% of chronic prostatitis patients, respectively, and to improve inflammatory symptoms in 54% of patients [12]. In a 2003 study comparing the efficacy of different NSAIDs in the treatment of chronic prostatitis [13], a total of 161 chronic prostatitis patients were randomized into three groups treated with 25 mg and 50 mg rofecoxib or placebo, respectively, for 6 weeks. The results indicated that treatment with 50 mg rofecoxib effected a statistical improvement in the quality of life of the patients. Collectively, these data indicate that treatment with NSAIDs might hold many benefits for chronic prostatitis patients.
4. Benign Prostate Hyperplasia
Recent in vitro and epidemiological evidence has shown that age, genetics, endocrine status, inflammation, and lifestyle are risk factors for BPH and/or lower urinary tract symptoms (LUTS) [14]. Inflammation has been linked with the development and progression of BPH [15, 16], and several studies have reported the presence of intraprostatic inflammatory infiltration in BPH tissues [17, 18]. The inflammatory cytokine IL-17, which is not expressed in normal prostate, has been shown to be expressed in inflammatory prostate [19]. Moreover, COX-1 and COX-2 are expressed in BPH tissues [20–23], and elevated COX-2 expression has been associated with increased levels of Bcl-2 and cell proliferation in BPH [23]. Given the inhibitory effect on COX-1 and COX-2 activity by NSAID treatment, would be anticipated to reduce the risk of BPH development and progression.
In a 2005 study [24], 46 patients with LUTS and BPH were divided to two groups and treated with finasteride only or finasteride+rofecoxib, respectively, for 24 weeks. Compared with the finasteride only group, patients in the finasteride+rofecoxib group had a higher decreasing of average international prostate symptom score (IPSS) after 4 weeks and faster overall relief of BPH symptoms. In another study, compared with LUTS and BPH patients treated with an α-blocker alone, patients treated with a COX-2 inhibitor + an α-blocker had a higher decreasing of average IPSS, quality of life (QoL) index, and overactive bladder symptoms score (OABSS) [25]. Jhang et al. showed that an α-blocker combined with celecoxib group decreased the IPSS score, but not significantly, compared to α-blocker monotherapy group [26]. Moreover, nocturia associated with LUTS has been shown to be improved by treatment with sedatives and analgesics, including COX-2 inhibitors [27].
Daily use of NSAIDs has been shown to result in improved urinary symptoms, increased urine flow rate, and decreased prostate volume and prostate-specific antigen levels [28]. In addition, administration of NSAIDs reportedly decreased both IPSS and mean nocturnal urination frequency, another well-known symptom of BPH, suggesting that NSAIDs are a novel option to improve symptoms of BPH [29]. While some studies have reported a lack of side effects associated with NSAID treatment [30], others have reported the opposite results. For example, in a cohort study of NSAID and risk of BPH, using 4,735 men without BPH as a baseline, Schenk et al. found that NSAIDs were not associated with the risk of BPH [31]. In contrast, other studies have reported that NSAIDs increased the risk of BPH [32, 33]. Moreover, acute urinary retention has been associated with the use of COX-2 selective NSAIDs but not with the use of nonselective NSAIDs [34].
While data are limited, several in vitro and in vivo studies have probed the mechanism(s) underlying the improvement in BPH and its symptoms effected by NSAIDs. Ibuprofen and aspirin, two commonly used NSAIDs, have been shown to decrease viability and suppress proliferation of BPH cell lines [35]. Moreover, certain animal models of BPH are characterized by elevated expression of the enzymes COX-2 and 5-lipoxygenase (5-LOX) that also regulates inflammation [36]. Treatment of these animals with a dual inhibitor of COX and 5-LOX decreased prostaglandin E2 levels and expression of the antiapoptotic factor Bcl-2 and increased expression of the proapoptotic factors Bax and caspase-9, resulting in the induction of apoptosis.
In summary, while the determining of the efficacy of NSAIDs in the treatment of BPH requires further clinical studies, in vitro evidence suggests that NSAIDs might be beneficial for alleviating symptoms in BPH patients and for reducing the risk of the development or progression of the disease in unaffected individuals.
5. Prostate Cancer
Inflammation arising from a variety of physiological insults is thought to be a major cause and promoter of various cancers, including prostate cancer [37–40]. Inflammation of the prostate is associated with the induction of cytokines, chemokines, and growth factors, as well as COX-2, which is also overexpressed in prostate cancer [21, 41]. Given their anti-inflammatory roles in the reduction of COX activity and prostaglandin synthesis, therefore [37, 42], it has been speculated that treatment with NSAIDs might reduce the risk of prostate cancer [43].
In vitro studies have provided evidence pointing to the suppression of prostate cancer development and progression by NSAIDs. For example, celecoxib, a COX-2 selective NSAID, has been shown to induce apoptosis in PC3 and LNCaP cells via inhibition of Akt and activation of caspase-3 [44, 45] and G1 arrest [46]. The fact that these cell lines do not express COX-2 indicates that celecoxib inhibits prostate cancer cell line growth via a COX-2 independent mechanism. In support of this notion, a celecoxib analog deficient in COX-2 inhibition has been shown to inhibit prostate cancer cell growth, also via repression of Akt and G1 arrest [46].
Other studies have investigated the relationship between NSAIDs, androgen signaling, and radiation therapy in the context of prostate cancer. Compared with parental LNCaP cells, LNCaP cells expressing COX-2 are more resistant to radiation therapy, and treatment with the COX-2 inhibitor diclofenac enhanced the effects of radiation therapy on these cells [47]. Similar results were also obtained in xenograft models [47]. NSAIDs have also been shown to delay the progression of prostate tumors from androgen-dependent to androgen-independent growth [48]. NSAIDs delayed the regrowth of LNCaP xenografts in castrated SCID mice. Another paper showed the possibility for the combination of hormone ablation therapy and NSAID treatment [49]. Celecoxib treatment increases the efficacy of androgen ablation therapy.
Studies of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which has elevated COX-2 expression and activity, further suggest the potential of NSAIDs in retarding prostate cancer development and progression. In this model, celecoxib suppresses expression of androgen receptor, COX-2, NFκB, and vascular endothelial growth factor (VEGF), reduces prostaglandin E2 levels, and increases levels of E-cadherin, α-catenin, and β-catenin [50, 51]. In the same model, celecoxib inhibits the development of prostatic intraepithelial neoplasia and adenocarcinoma in the prostate in a dose-dependent manner [52, 53]. The net effect of celecoxib in this model is to suppress invasion and metastasis, induce apoptosis, and enhance overall survival. NSAIDs have also been shown to increase cell cycle arrest and apoptosis via regulation of cell cycle regulatory protein in an animal model of chemical induction of prostate cancer [53]. Collectively these experimental reports suggest that NSAIDs may be beneficial for the treatment of advanced prostate cancer.
By virtue of their decreased side effects, NO-NSAIDs are gaining attention as an alternative to classical NO-NSAIDs side effects. NO-NSAIDs have been shown to inhibit cancer cell growth [10] and, in prostate cancer cells specifically, have proapoptotic and anti-invasive properties which exceed those of classical NSAIDs [54–57]. Moreover, NO-NSAIDs directly inhibit hypoxia-inducible factor-1α (HIF-1α), a transcriptional activator of VEGF, and other cancer-related genes [58]. Based on these and other studies, NO-NSAIDs show considerable potential as an alternative to classical NSAIDs for the treatment of prostate cancer.
Although in vitro studies point to the ability of NSAIDs to protect against cancer progression, results from clinical studies are more inconsistent. Many studies have linked NSAIDs with a reduced risk of prostate cancer [59–64]. For example, aspirin and other NSAIDs have been shown to decrease plasma prostate serum antigen (PSA) levels and to reduce the risk of prostate cancer (OR 0.82, 95% CI 0.68–0.99). Daily use of aspirin also reduced further prostate cancer risk. Smith et al. investigated the effect of NSAIDs on serum PSA after radical prostatectomy or radiation therapy in 78 men randomly divided into placebo (40 men) and celecoxib (38 men) groups. Relative to the placebo group, individuals in the celecoxib group had a 2-fold higher PSA doubling time and significantly decreased PSA velocity [61]. Moreover, combination treatment with an α1-blocker and COX-2 inhibitor has been shown to decrease serum PSA in 53.3% of patients [26]. In addition, administration of 200 mg celecoxib twice daily to 20 patients who had undergone radical prostatectomy or radiation therapy effected a reduction in serum PSA in 60% of individuals [65]. In further support of these findings, daily consumption of more than six aspirins has been shown to reduce prostate cancer risk (OR 0.76, 95% CI 0.60–0.98) [60]. In contrast, other studies have failed to associate aspirin with a reduced risk of prostate cancer [66, 67], and one has suggested that treatment with NSAIDs increases the risk of prostate cancer (odds ratio (OR) 1.33, 95% confidence interval (95% CI) 1.07 to 1.64) [68]. Interestingly, Leitzmann et al. indicated that, while aspirin reduced the risk of metastatic prostate cancer risk, it did not protect against the risk of prostate cancer [69]. Based on these observations, the association between NSAIDs and prostate cancer risk requires further study.
6. Conclusions
Many studies have demonstrated a link between inflammation and prostatic diseases, such as BPH and prostate cancer. Although there are some suggestions that NSAIDs increase the risk of prostatic diseases, most of studies suggest that NSAIDs have potential to improve symptoms in, and reduce the risk of, prostatic diseases.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
SchrecengostR.KnudsenK. E.Molecular pathogenesis and progression of prostate cancer201340324425810.1053/j.seminoncol.2013.04.001PennaG.MondainiN.AmuchasteguiS.InnocentiS. D.CariniM.GiubileiG.FibbiB.ColliE.MaggiM.AdoriniL.Seminal plasma cytokines and chemokines in prostate inflammation: interleukin 8 as a predictive biomarker in chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia20075125245332-s2.0-3384557030010.1016/j.eururo.2006.07.016MacoskaJ. A.Chemokines and BPH/LUTS2011824-52532602-s2.0-8005296356910.1016/j.diff.2011.04.003CaiT.MazzoliS.MeacciF.BoddiV.MondainiN.MalossiniG.BartolettiR.Epidemiological features and resistance pattern in uropathogens isolated from chronic bacterial prostatitis20114934484542-s2.0-7995972470810.1007/s12275-011-0391-zVaneJ. R.Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs1971231252322352-s2.0-0015237292DuBoisR. N.AbramsonS. B.CroffordL.GuptaR. A.SimonL. S.van de PutteL. B. A.LipskyP. E.Cyclooxygenase in biology and disease19981212106310732-s2.0-0031689543VaneJ. R.BakhleY. S.BottingR. M.Cyclooxygenases 1 and 2199838971202-s2.0-0031777185BombardierC.LaineL.ReicinA.ShapiroD.Burgos-VargasR.DavisB.DayR.FerrazM. B.HawkeyC. J.HochbergM. C.KvienT. K.SchnitzerT. J.Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis200034321152015282-s2.0-003470710510.1056/NEJM200011233432103BresalierR. S.SandlerR. S.QuanH.BologneseJ. A.OxeniusB.HorganK.LinesC.RiddellR.MortonD.LanasA.KonstamM. A.BaronJ. A.Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial200535211109211022-s2.0-1974438077610.1056/NEJMoa050493RigasB.KashfiK.Nitric-oxide-donating NSAIDs as agents for cancer prevention20041073243302-s2.0-304283737310.1016/j.molmed.2004.05.004KriegerJ. N.NybergL.Jr.NickelJ. C.NIH consensus definition and classification of prostatitis199928232362372-s2.0-003359189910.1001/jama.282.3.236CanaleD.ScaricabarozziI.GiorgiP.TurchiP.DucciM.Menchini-FabrisG. F.Use of a novel non-steroidal anti-inflammatory drug, nimesulide, in the treatment of abacterial prostatovesiculitis19932531631662-s2.0-0027212996NickelJ. C.PontariM.MoonT.GittelmanM.MalekG.FarringtonJ.PearsonJ.KrupaD.BachM.DriskoJ.A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis20031694140114052-s2.0-003737629910.1097/01.ju.0000054983.45096.16ParsonsJ. K.Benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors2010542122182-s2.0-7795626139410.1007/s11884-010-0067-2NickelJ. C.Inflammation and benign prostatic hyperplasia20083511091152-s2.0-3644897549310.1016/j.ucl.2007.09.012ChughtaiB.LeeR.TeA.KaplanS.Role of inflammation in benign prostatic hyperplasia2011133147150KohnenP. W.DrachG. W.Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study197912167557602-s2.0-0018765076di SilverioF.GentileV.de MatteisA.MariottiG.GiuseppeV.LuigiP. A.SciarraA.Distribution of inflammation, pre-malignant lesions, incidental carcinoma in histologically confirmed benign prostatic hyperplasia: a retrospective analysis20034321641752-s2.0-003732609810.1016/S0302-2838(02)00548-1SteinerG. E.NewmanM. E.PaiklD.StixU.Memaran-DagdaN.LeeC.MarbergerM. J.Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate20035631711822-s2.0-004166959410.1002/pros.10238O'NeillG. P.Ford-HutchinsonA. W.Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues199333021561602-s2.0-0027293391KirschenbaumA.KlausnerA. P.LeeR.UngerP.YaoS.LiuX.-H.LevineA. C.Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate20005646716762-s2.0-003382916010.1016/S0090-4295(00)00674-9LeeL.-M.PanC.-C.ChengC.-J.ChiC.-W.LiuT.-Y.Expression of cyclooxygenase-2 in prostate adenocarcinoma and benign prostatic hyperplasia2001212129112942-s2.0-0035011423WangW.BerghA.DamberJ.-E.Chronic inflammation in benign prostate hyperplasia is associated with focal upregulation of cyclooxygenase-2, Bcl-2, and cell proliferation in the glandular epithelium200461160722-s2.0-414310911910.1002/pros.20061di SilverioF.BosmanC.SalvatoriM.AlbanesiL.PannunziL. P.CiccarielloM.CardiA.SalvatoriG.SciarraA.Combination therapy with rofecoxib and finasteride in the treatment of men with Lower Urinary Tract Symptoms (LUTS) and Benign Prostatic Hyperplasia (BPH)200547172792-s2.0-964427248810.1016/j.eururo.2004.08.024OzdemirI.BozkurtO.DemirO.AslanG.EsenA. A.Combination therapy with doxazosin and tenoxicam for the management of lower urinary tract symptoms20097424314352-s2.0-6765110264810.1016/j.urology.2009.01.088JhangJ.-F.JiangY.-H.KuoH.-C.Adding cyclooxygenase-2 inhibitor to alpha blocker for patients with benign prostate hyperplasia and elevated serum prostate specific antigen could not improve prostate biopsy detection rate but improve lower urinary tract symptoms201367121327133310.1111/ijcp.12220KayeM.Aging, circadian weight change, and nocturia20081091p11p182-s2.0-4634910115610.1159/000129653St. SauverJ. L.JacobsonD. J.McgreeM. E.LieberM. M.JacobsenS. J.Protective association between nonsteroidal antiinflammatory drug use and measures of benign prostatic hyperplasia200616487607682-s2.0-3374946034110.1093/aje/kwj258FalahatkarS.MokhtariG.PourrezaF.AsgariS. A.KamranA. N.Celecoxib for treatment of nocturia caused by benign prostatic hyperplasia: a prospective, randomized, double-blind, placebo-controlled study20087248138162-s2.0-5294913132710.1016/j.urology.2008.04.069KahokehrA.VatherR.NixonA.HillA. G.Non-steroidal anti-inflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials2013111230431110.1111/j.1464-410X.2012.11559.xSchenkJ. M.CalipG. S.TangenC. M.GoodmanP.ParsonsJ. K.ThompsonI. M.KristalA. R.Indications for and use of nonsteroidal antiinflammatory drugs and the risk of incident, symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial2012176215616310.1093/aje/kwr524MeigsJ. B.MohrB.BarryM. J.CollinsM. M.McKinlayJ. B.Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men20015499359442-s2.0-003488314310.1016/S0895-4356(01)00351-1KangD.AndrioleG. L.van de VoorenR. C.CrawfordD.ChiaD.UrbanD. A.RedingD.HuangW.-Y.HayesR. B.Risk behaviours and benign prostatic hyperplasia2004939124112452-s2.0-294274664410.1111/j.1464-410X.2004.04839.xVerhammeK. M. C.DielemanJ. P.van WijkM. A. M.van der LeiJ.BoschJ. L. H. R.StrickerB. H. C.SturkenboomM. C. J. M.Nonsteroidal anti-inflammatory drugs and increased risk of acute urinary retention200516513154715512-s2.0-2304445117210.1001/archinte.165.13.1547MinneryC. H.GetzenbergR. H.Benign prostatic hyperplasia cell line viability and modulation of JM-27 by doxazosin and ibuprofen200517413753792-s2.0-2044444553010.1097/01.ju.0000161598.24740.34AltavillaD.MinutoliL.PolitoF.IrreraN.ArenaS.MagnoC.RinaldiM.BurnettB. P.SquadritoF.BittoA.Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia201216719510810.1111/j.1476-5381.2012.01969.xKashiwagiE.ShiotaM.YokomizoA.ItsumiM.InokuchiJ.UchiumiT.NaitoS.Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells201320343144110.1530/ERC-12-0344de MarzoA. M.PlatzE. A.SutcliffeS.XuJ.GrönbergH.DrakeC. G.NakaiY.IsaacsW. B.NelsonW. G.Inflammation in prostate carcinogenesis2007742562692-s2.0-3394768785410.1038/nrc2090SfanosK. S.de MarzoA. M.Prostate cancer and inflammation: the evidence20126011992152-s2.0-8425520445710.1111/j.1365-2559.2011.04033.xHaverkampJ.CharbonneauB.RatliffT. L.Prostate inflammation and its potential impact on prostate cancer: a current review20081035134413532-s2.0-4174908328410.1002/jcb.21536GuptaS.SrivastavaM.AhmadN.BostwickD. G.MukhtarH.Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma20004217378MajimaM.AmanoH.HayashiI.Prostanoid receptor signaling relevant to tumor growth and angiogenesis200324105245292-s2.0-014191883810.1016/j.tips.2003.08.005VeitonmäkiT.TammelaT. L.AuvinenA.MurtolaT. J.Use of aspirin, but not other non-steroidal anti-inflammatory drugs is associated with decreased prostate cancer risk at the population level201349493894510.1016/j.ejca.2012.09.030PatelM. I.SubbaramaiahK.DuB.ChangM.YangP.NewmanR. A.Cordon-CardoC.ThalerH. T.DannenbergA. J.Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism2005115199920072-s2.0-1634438999310.1158/1078-0432.CCR-04-1877HsuA.-L.ChingT.-T.WangD.-S.SongX.RangnekarV. M.ChenC.-S.The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-220002751511397114032-s2.0-003464668810.1074/jbc.275.15.11397KulpS. K.YangY.-T.HungC.-C.ChenK.-F.LaiJ.-P.TsengP.-H.FowbleJ. W.WardP. J.ChenC.-S.3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells2004644144414512-s2.0-124227120810.1158/0008-5472.CAN-03-2396InoueT.AnaiS.OnishiS.MiyakeM.TanakaN.HirayamaA.FujimotoK.HiraoY.Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model201313, article 110.1186/1471-2490-13-1ZhengX.CuiX.-X.GaoZ.ZhaoY.LinY.ShihW. J.HuangM.-T.LiuY.RabsonA.ReddyB.YangC. S.ConneyA. H.Atorvastatin and celecoxib in combination inhibits the progression of androgen-dependent LNCaP xenograft prostate tumors to androgen independence2010311141242-s2.0-7764919595110.1158/1940-6207.CAPR-09-0059AbedinpourP.BaronV. T.WelshJ.BorgströmP.Regression of prostatetumors upon combination of hormone ablation therapy and celecoxib in vivo20117188138232-s2.0-7995367601510.1002/pros.21297NarayananB. A.NarayananN. K.PittmanB.ReddyB. S.Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model20041022772777372-s2.0-934422515510.1158/1078-0432.CCR-04-0732GuptaS.AdhamiV. M.SubbarayanM.MacLennanG. T.LewinJ. S.HafeliU. O.FuP.MukhtarH.Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model2004649333433432-s2.0-234262540310.1158/0008-5472.CAN-03-2422NarayananB. A.NarayananN. K.PttmanB.ReddyB. S.Adenocarcina of the mouse prostate growth inhibition by celecoxib: downregulation of transcription factors involved in COX-2 inhibition20066632572652-s2.0-3194444703010.1002/pros.20331NarayananB. A.CondonM. S.BoslandM. C.NarayananN. K.ReddyB. S.Suppression of N-methyl-N-nitrosourea/testosterone-induced rat prostate cancer growth by celecoxib: effects on cyclooxygenase-2, cell cycle regulation, and apoptosis mechanism(s)200399350335132-s2.0-0041833663RoyleJ. S.RossJ. A.AnsellI.BollinaP.TullochD. N.HabibF. K.Nitric oxide donating nonsteroidal anti-inflammatory drugs induce apoptosis in human prostate cancer cell systems and human prostatic stroma via caspase-3200417213383442-s2.0-3242778622HugueninS.Fleury-FeithJ.KheuangL.JaurandM.-C.BollaM.RiffaudJ.-P.ChopinD. K.VacherotF.Nitrosulindac (NCX 1102): a new nitric oxide-donating non-steroidal anti-inflammatory drug (NO-NSAID), inhibits proliferation and induces apoptosis in human prostatic epithelial cell lines20046121321412-s2.0-454429347610.1002/pros.20081StewartG. D.NandaJ.BrownD. J. G.RiddickA. C. P.RossJ. A.HabibF. K.NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway200912412232322-s2.0-5814938870910.1002/ijc.23934LuW.TinsleyH. N.KeetonA.QuZ.PiazzaG. A.LiY.Suppression of Wnt/β-catenin signaling inhibits prostate cancer cell proliferation200960218142-s2.0-5724910818810.1016/j.ejphar.2008.10.053SemenzaG. L.Targeting HIF-1 for cancer therapy20033107217322-s2.0-0142166332NelsonJ. E.HarrisR. E.Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study2000711691702-s2.0-0033631452HabelL. A.ZhaoW.StanfordJ. L.Daily aspirin use and prostate cancer risk in a large, multiracial cohort in the US20021354274342-s2.0-003598776510.1023/A:1015788502099SmithM. R.ManolaJ.KaufmanD. S.OhW. K.BubleyG. J.KantoffP. W.Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy20062418272327282-s2.0-3374556353110.1200/JCO.2005.03.7804NorrishA. E.JacksonR. T.McRaeC. U.Non-steroidal anti-inflammatory drugs and prostate cancer progression1998774511515SalinasC. A.KwonE. M.FitzgeraldL. M.FengZ.NelsonP. S.OstranderE. A.PetersU.StanfordJ. L.Use of aspirin and other nonsteroidal antiinflammatory medications in relation to prostate cancer risk201017255785902-s2.0-7795624009210.1093/aje/kwq175RobertsR. O.JacobsonD. J.GirmanC. J.RhodesT.LieberM. M.JacobsenS. J.A population-based study of daily nonsteroidal anti-inflammatory drug use and prostate cancer20027732192252-s2.0-0036183346PruthiR. S.DerksenJ. E.MooreD.A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy20049332752782-s2.0-134231004810.1111/j.1464-410X.2004.04601.xMenezesR. J.SwedeH.NilesR.MoysichK. B.Regular use of aspirin and prostate cancer risk (United States)20061732512562-s2.0-3294445955710.1007/s10552-005-0450-zBosettiC.TalaminiR.NegriE.FranceschiS.MontellaM.la VecchiaC.Aspirin and the risk of prostate cancer200615143452-s2.0-3004443970610.1097/01.cej.0000180665.04335.deLangmanM. J. S.ChengK. K.GilmanE. A.LancashireR. J.Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database20003207250164216462-s2.0-0034679222LeitzmannM. F.StampferM. J.MaJ.ChanJ. M.ColditzG. A.WillettW. C.GiovannucciE.Aspirin use in relation to risk of prostate cancer20021110110811112-s2.0-0036801502