Association between phosphodiesterase type 5 inhibitors and prostate cancer:

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LITERATURE REVIEW

Association between phosphodiesterase type 5 inhibitors and prostate cancer:

A systematic review

Association inhibiteurs de la Phosphodiestérase type 5 et cancer de la prostate : revue systématique de la littérature

Fouad Aoun

^a^,^b^,∗

, Amine Slaoui

^a^,^c

,

Al Hajj Obeid Walid

^d

, Simone Albisinni

^d

, Grégoire Assenmacher

^a

, Elea de Plaen

^a^,^d

, Jean-Michel Azzo

^e

, Alexandre Peltier

^a

, Thierry Roumeguère

^d

aServiced’urologie,institutJules-Bordet,universitéLibredeBruxelles,Bruxelles,Belgique

bServiced’urologie,hôtelDieu-de-France,universitéSaint-Joseph,Beyrouth,Liban

cServiceurologieBhôpitalavicenne,universitéMohamed-V,Rabat,Maroc

dServiced’urologie,cliniquesuniversitairesdeBruxelles,hôpitalErasme,université Libre-de-Bruxelles,Bruxelles,Belgique

eServiced’urologie,hôpitalMont-Liban,universitéLibano-Américaine,Beyrouth,Liban

Received19February2018;accepted17July2018 Availableonline7September2018

KEYWORDS PDE5inhibitors;

ProstateCancer;

Radical prostatectomy

Summary

Introduction.—Weaimtoassesstheeffectofphosphodiesterasetype5inhibitors(PDE5I)on prostatecancerriskaswellonbiochemicalrecurrenceafterradicalprostatectomy.

Method.—Weperformedaresearchusingthefollowingkeywords‘‘Phosphodiesterasetype5 inhibitors’’and‘‘Prostatecancer’’.OnlytrialsexaminingtheeffectofPDE5Ionprostatecancer riskandrecurrenceafterradicalprostatectomywereincluded.

∗Correspondingauthor.Serviced’urologie,institutJules-Bordet,1,rueHéger-Bordet,1000Bruxelles,Belgique.

E-mailaddress:fouad.aoun@bordet.be(F.Aoun).

https://doi.org/10.1016/j.purol.2018.07.004

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Results Seventeenpreclinicaltrialsandsevenclinicaltrialswereincluded.Preclinicalstudies demonstrateapivotalroleforPDE5Iasamodulatorofapoptosispreventingprostatecarcino- genesis.TheclinicalbeneﬁtofPDE5Iwasnotdemonstrated.PDE5Iusewasnotassociatedwith decreasedprostatecancerdiagnosisintworetrospectivecohortstudies.Biochemicalrecur- renceafterradicalprostatectomywasnotlower(norhigher)inpatientstakingPDE5Iinthree retrospectivecasematchstudies.

Conclusion.—Basedonthisreview,achangeinourpracticeregardingpharmacologicalreedu- cationafterradicalprostatectomyisnotjustiﬁed.

MOTSCLÉS Inhibiteursdela Phosphodiesterase type5;

Cancerdela prostate;

Prostatectomietotale

Résumé

Introduction.—Lebutdecetterevueestderevoirl’implicationéventuelledesinhibiteursde phosphodiestérasedetype5(IPDE5)danslagenèseetlaprogressionducancerdelaprostate.

Matérieletméthode.—Unerechercheaétémenée,endécembre2017,surlabasedesdonnées usuellesenutilisantlesmots-cléssuivant:«Phosphodiesterasetype5inhibitors»et«Prostate cancer».Seulslesessaisprécliniquesetcliniquesexaminantuneassociationentrelaprisedes IPDE5etlagenèseet/oulaprogressionducancerdelaprostateétaientinclus.

Résultats.—Dix-septétudesprécliniquesetseptétudescliniquesontétéretenues.Lesétudes cliniquesplaidentenfaveurd’uneffetprotecteurdesIPDE5contrelecancerdelaprostate.

Lebénéﬁcecliniquedecetteassociationestcontradictoire.Lasynthèsedesdonnéesmontre l’absenced’unrisqueaccruderécidivebiologiquechezlesutilisateurs.Iln’yapasnonplus uneassociationentrelaprisedesIPDE5etlerisquededévelopperuncancerdelaprostate.

Conclusion.—Ensebasantsurcetterevue,unemodiﬁcationdenotrepratiqueconcernantla rééducationpharmacologiqueaprèsprostatectomietotalen’estpasjustiﬁée.Iln’yapasnon plusd’évidenceàutilisercegenredetraitementenpréventionprimaireousecondairedansle cancerdelaprostate.

Introduction

Prostatecanceristhemostcommoncancerfoundinmen.

Itrepresentsnearly26%ofallmalecancers.Theprognosis ofthiscancerremainsexcellentandsurvivalat10yearsfor localized stages is around90% [1]. Mostoften, treatment with curative intent consists of a radical prostatectomy with preservation of neurovascular bundles after taking into account the age of patient and the characteristics of the tumor [1].However, thissurgery is responsible for functional complications that impair the patient’s quality of life. Erectile dysfunctionis the most commonencoun- tered complication with an incidence varying between 25 and 75% depending on the series [2]. A postoperative management or early pharmacologic rehabilitation may be proposed and most often uses phosphodiesterase type 5 inhibitors (PDE5I). PDE5I leads to increased con- centrations of cyclic guanosine monophosphate (cGMP)in the muscle cell inducing relaxation of smooth muscles in cavernous bodiespromotingbloodﬂow andcavernous tissue oxygenation. This oxygenation willprevent ﬁbrosis in cavernous bodies, apoptosis of smooth muscle cells and veno-occlusive dysfunction [3]. Manyclinical studies sup- portthisprincipleofearlypharmacologicrehabilitationwith animprovementoferectionsandqualityoflifeinpatients

after radical prostatectomy. Recently, the impact of tak- ingPDE5Ionthedevelopment,progressionandrecurrence of prostate cancer has been evoked. Several preclinical and clinical studies have evaluated this association with conﬂictingresults. The purposeof this review is toiden- tify the possible implication of phosphodiesterase type 5 inhibitorsin thedevelopmentand progressionof prostate cancer.

Material and methods Research Strategy

AwebsearchwasconductedduringDecember2017based onPubmeddata,EmbaseandCochraneBookstore.Theuse ofﬁltersmadeitpossibletolimitthesearchtopreclinical andclinicaltrials writtenin eitherEnglish orFrench. The keywordsused(MesHlanguage)were:‘‘Phosphodiesterase type5inhibitors’’and‘‘Prostatecancer’’.

Selection of articles (PICO/PRISMA method)

The eligibility of articles was deﬁned using the PICOS method,inconcordancewiththePRISMArecommendations:

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Participants (P), Interventions (I), Comparators (C), Out- comes(O)andStudyDesign(S)[4].Anarticlewasconsidered relevant for this review of the literature if it evaluated:

apopulationat risk ofdevelopingprostate cancer orhav- ing hadprostate cancer treated with curative intent (P);

treatedwithPDE5inhibitors(I);comparedtheassociation withprostatecancerortheoncologicaloutcomeaftercura- tivetreatment(C);in termsof incidenceandbiochemical recurrence(O).Only30originalarticles,preclinicalresearch articlesandclinicalstudieshavebeenincludedinthisreview (S).Articlesreportingonlythefunctionalresultshavebeen omitted.The seriesof prospective or retrospective cases without comparison arms but with reported oncological resultswereretained.Twooftheauthors(GA,AS)reviewed alltheabstractsandselectedtherelevantarticles.These werefullyreadbyathirdauthor(FA)beforeproceedingto ﬁnaleligibility.

Extraction of data

Dataextractionwasperformedbytwoauthors(GA,AS).The datacollectedwerearrangedbytypeof study,countryof origin,timeintervalandthedateofpublication.Thequal- ityof studies, the number of patients,the presence of a comparisonarm,theincidenceofprostatecancerandthe oncologyresultswerealsoreported.

Evaluation of the quality of studies and level of proof

Randomizedclinical trials wereevaluatedby their adher- encetothe CONSORT2010 checklist [5]. Non-randomized trials(case-control studiesor case series)were evaluated usingtheNewcastle-Ottawascale.This scalegivesascore withstarsaccordingtothequalityoftheselection(4stars), thecomparabilitybetweenselectedpopulationandthecon- trolgroup(2stars),andtheﬁndingofresultsinrelationto the exposure (3stars). The maximum score being 9stars, a study with a score≥7 was considered of good quality.

Thelevelofevidenceprovidedbyeachstudywasreported following the recommendations of the Oxford Center for Evidence-BasedMedicine[6].

Results and discussion Selected articles

Seventeen pre-clinical and seven clinical trials (Table 1) wereincludedintheﬁnalsynthesis(Fig.1).Amongclinical trials,noprospectiverandomizedtrial andnoprospective studywere foundin theliterature. The sevenclinical tri- alswereretrospectivecase-controlstudies,comparingthe effectof PDE5 inhibitors on development, progression or biochemicalrecurrenceofprostatecancer.

Phosphodiesterase type 5 is expressed in prostatic tissue

PDE5isanenzymeresponsibleforthedegradationofcyclic guanosine monophosphate (cGMP), the second intracellu- larmessenger of nitric oxide(NO). This enzymeis mainly presentinthesmoothmuscleofthecorporacavernosa.It hasalsobeen identiﬁedinthesmoothmusclecells ofthe genitourinarytractespeciallyatthelevelofthebladder[7].

Uckert andal. had used immunoﬂuorescence toestablish

itspresenceintheprostate [8].This enzymeisalsofound in the stroma and glandular structures of the transition zone of the prostate. Zenzmaieret al.had demonstrated the presenceof this enzyme inthe fibro-muscularstroma mainly [9]. Two other studies haddemonstrated that this enzymeis presentinthefibro-musculartissuebutismore abundant inendothelialcellsandprostaticsmoothmuscle cells [10,11]. This latter resultwas validated bytwo ani- malstudiesexaminingthistimetheentireprostateandnot onlytissuefromthetransitionalzoneorthefibro-muscular stroma[12,13].TheexpressionofPDE5isindeedseenmainly in thejuxta-glandular musclecells andtoa lesserextent in theglandularepithelium andendothelial cells[7].This enzyme plays a key role in determining levels of cGMPs that have an impacton the relaxation of smooth muscle cells.

Role of phosphodiesterase type 5 in prostate carcinogenesis

The importance of the NO/cGMP signaling pathway in carcinogenesis had lead several teams to investigate the expressionofPDE5withintumorsandthepotentialimpact ofitsinhibitionondevelopment,growth,proliferationand progression of cancer cells. Early studies had observed overexpression of PDE5 in human carcinomas (squamous cellcarcinomaandtransitionalbladdercarcinomacompar- atively to normal urothelium) as well as at the level of animal tumorsin comparisonwithnormalhomologoustis- sues[14].PDE5hadalsobeenidentiﬁedasthepredominant isoforminmanycelllinesofcarcinomasinculture,includ- ingprostatecancer(LNCAP,PC3lines)[15].Directevidence ofPDE5involvementincellgrowthregulationandapoptosis oftumorousprostaticcellsariseononehandfromstudies onthepre-apoptoticeffectsandinhibitorsoftumorgrowth ofNO/cGMP,andsecondly,ofitsresistancetohypoxia[16].

Indeed, NO is a molecule that induces apoptosiswhen it is produced at high doses. Cellular hypoxia induces inhibition of the intracellular signaling pathway mediated by NO-cGMPandtransformsprostatecancercellsintoincreas- ingly aggressive cells [17,18]. Another mechanism is the involvement ofPDE5 in theHippo signalingpathway [15].

This pathway plays a crucial role in inhibiting contact between cancer cells,itsalteration beingstronglyassoci- ated with malignant manifestations. The authors suggest that in vitro inhibition of PDE5 may improve the differ- entiation and make prostatic stem cells less resistant to chemotherapy[19].

Role of PDE5 inhibitors on prostate carcinogenesis

A potential association between PDE5 inhibitors and prostate cancerprogressiondatesback tothe early2000s when severalpreclinical studies have suggested a protective effect. Suppression of human prostatic cell growth in a mouse model was made possible through the use of Exisulind an anti-cancer agentderivative of Sulindac that inhibits PDE5 [20,21]. In a similar study, a low dose of Exisulind combined with a typical type 2 cyclooxygenase inhibitoractuallyhadinhibitedtumorgrowthbyimproving apoptosis [22]. Seraﬁni et al. had demonstrated stimu- lation of anti-tumor immunity by increasing nitric oxide andargininebyPDE5inhibitors[23].More recently,ithad been shownthatthePDE5enzymewasstronglyexpressed in the prostatic stroma and only low doses of inhibitors were able to inhibit the proliferation of stromal cells

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Table1 ClinicalstudiesinvestigatingtheimpactofPDE5Ionthedevelopmentofprostatecancerandonbiochemical recurrenceafterprimarytreatmentwithacurativeintent.

Designofthe study(author, country)

Dateof publication (studyinterval)

Levelof evidence

Qualityof thestudy

Totalnumber ofpatients

Impactonthe developmentof prostatecancer

Impacton biochemical recurrence Rcase-match

(Chavez, Etats-Unis)

2013 (2000—2006)

3b 5 4974 Lessriskto

developprostate cancerinthe grouptreated withPDE5I Rcase-match

(Jamnager- walla, Etats-Unis)

2016 (2003—2009)

3b 7 6501 Noassociation

Rcase-match (LukeMachen, Etats-Unis)

2017 (2000—2011)

Rcase-match (Michl, Allemagne)

2015 (2000—2010)

3b 6 4752 Increased

biochemical recurrencein thegroup treatedwith PDE5I Rcase-match

(Gallina,Italie) 2015 (2004—2013)

Rcase-match(Jo, Coréedesud)

2016 (2005—2014)

Rcase-match (Loeb,Suède)

2016 (2006—2007)

Figure1. Flowchartindicatingthestrategyofresearch,screeningandselectionofarticleforoursystematicreviewoftheliterature.

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[9]. By resistinghypoxia, PDE5I were also able to atten- uate the proliferation of human prostate cancer cells in an animal model [17]. Indeed, cellular hypoxia induces an inhibition of the intracellular signaling pathway medi- atedbyNO-cGMPandtransformsprostatecancercellsinto chemotherapy-resistantcells,capableofescapingimmuno- surveillance.TreatmentwithPDE5Icould,accordingtothe authors make cancerous prostatic cells less resistant to chemotherapy.

Das et al. had demonstrated, in an in vitro study, an increaseintheanti-tumoractivityofDoxorubicininprostate cancercellstreatedwithPDE5I[24].Thustheyhavefound anincrease inthegenerationof freeradicalsandoverex- pressionofcaspase3,anenzymethatplaysacentralrole in cell apoptosis adding toa reduction in the expression ofBcl-xL, an anti-apoptotic protein.A morerecent study conductedbythesameteam,hadhighlightedanewmech- anismofsynergy betweenPDE5inhibitorsandDoxorubicin involvingNF-␬Binactivationassociatedwithanti-apoptotic factorsinprostaticcellsexpressingCD95[25].Byincreasing theinﬂuxintumoraltissues,PDE5Icouldplayafacilitating roleincombinationwithotheranti-cancermoleculesallow- ingthemabetterintra-tumoralpenetrationandrestoration oftheircytotoxicand/orimmunomodulatoryactivities.

The clinical impact of PDE5 inhibitors on the development of prostate cancer

In 2013, a retrospective study had shown a reduced incidence of prostate cancer in patients treated with PDE5 inhibitors[26].Ofthe4974patientssufferingfromerectile dysfunction,patientstreatedwithPDE5Ihada60%reduc- tioninriskofdevelopingprostatecancerduringthecourse of the study (OR=0.4, 95% CI: 0.3—0.5). This association betweentakingPDE5Iandthereducedriskofprostatecan- cercouldberelatedtoincreasedejaculatoryfrequencyin treated patients compared to patients with erectile dys- functionwithoutpharmacologictreatment. This increased ejaculatoryfrequencyhadbeensigniﬁcantlyassociatedwith areducedrisk ofprostate cancerin thelargeprospective cohortofLeitzmann[27].

However,amorerecentcohortstudywithcase-control haddemonstratednoassociationbetweentheuseofPDE5I andprostatecancerrisk[28].

Inthisstudy,55.6%ofpatientswhodevelopedprostate cancer were on PDE5 inhibitors. In the group that did notdevelopprostate cancer57.4%ofpatients wereunder PDE5I. A secondary analysis of the recently published

‘‘REDUCE’’ trial had also demonstrated the lack of association between the use of PDE5I and prostate cancer risk [29]. In this study, men withnegative prostate biop- sies were included and repeated biopsy at 2 and 4 years.Thedetection rateof prostatecancer in thisstudy was 19.5% in patients treated with PDE5I vs. 22.7% in patientsnotreceivingPDE5I(OR=0.83,95%CI0.63—1.08, P=0.161).Nostatisticallysigniﬁcantassociationwasfound between taking PDE5inhibitors and the aggressiveness of cancer.

The clinical impact of PDE5 inhibitors use on progression and biochemical recurrence in prostate cancer

The abundancy of preclinical data on the potential protective effect of PDE5 inhibitors onprostate cancer cells had stimulated several teams to examine the impact of

thesePDE5Ionbiochemicalrecurrenceafterradicalprosta- tectomy. A ﬁrst study by the team of the Martini Clinic in Germany had found an increase in biochemical recur- renceafterradicalprostatectomyinpatientstreatedwith PDE5Icompared topatientsnot taking PDE5I[30].Out of the4752patientsincludedinthestudyandfollowedfora median of5years,1110patients hadreceivedPDE5Ipost- operatively. In multivariate analysis, intake of PDE5I was an independent risk factor of biochemicalrecurrence(RR 1.38,95%CI:1.11—1.70,P=0.0035).Anotherretrospective analysisof acohort of2579 patientswitha detaileddata taking into accountthe dose and frequency of PDE5I had revealed contradictory results [31].In this study, the use of PDE5I on demand or in daily dose was not associated withbiochemicalrecurrenceat5years.Thenumberofpills takenbythepatientwasnotariskfactor forbiochemical recurrenceafterradical prostatectomy.AKoreanstudy of 1082 patientshadfound similarresults [32].Inthisstudy, the duration of use and the type of PDE5 inhibitor used as well as the delay before initiating this pharmacologic rehabilitation after surgery were not risk factors for biochemical recurrence. Moreover, a large study of prostate cancer registry in Sweden and the register of prescribed drugsdemonstratedthelackofassociationbetweentheuse ofPDE5Iandbiochemicalrecurrenceafterradicalprostate- ctomy(OR0.78,95%CI:0.59—1.03)orprimaryradiotherapy (OR 0.98.95% CI: 0.49—1.97) [33]. On the basis of these data,itseemsthereisnoassociationbetweentakingPDE5I after radical prostatectomy and the risk of biochemical recurrence.

Conclusion

Preclinical trialsdemonstrate a protective effect of PDE5 inhibitors against the development and progression of prostate cancer. However,clinicalevidenceof thisassoci- ationhasnotbeendemonstrated.Therealsodoesnotseem to bean increased risk of biochemical recurrenceamong PDE5I users. Amodiﬁcation of ourpractice in relation to pharmacologicrehabilitationafterradicalprostatectomyis notjustiﬁed. Thereisalsonoevidencetousethiskind of treatmentforprimaryorsecondarypreventionofprostate cancer

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]RozetF,Hennequin C,BeauvalJ-B, Beuzeboc P,CormierL, Fromont G, et al. CCAFU french national guidelines 2016- 2018 on prostate cancer. Progres En Urol J Assoc Fr Urol Soc Fr Urol 2016;27(Suppl 1):S95—143, http://dx.doi.org/

10.1016/S1166-7087(16)30705-9.

[2]Salonia A, Burnett AL, Graefen M, Hatzimouratidis K, Montorsi F, Mulhall JP, et al. Prevention and management of postprostatectomy sexual dysfunctions part 2:

recovery and preservation of erectile function, sexual desire, and orgasmic function. Eur Urol 2012;62:273—86, http://dx.doi.org/10.1016/j.eururo.2012.04.047.

[3]Aoun F, Albisinni S, Chemaly AK, Zanaty M, Roumeguère T. In Search for a Common Pathway for Health Issues in

(6)

Men–theSignofaHolmesian Deduction. AsianPac JCancer Prev2016;17:1—13.

[4]LiberatiA, Altman DG,Tetzlaff J, Mulrow C, GøtzschePC, IoannidisJPA,etal.ThePRISMAstatementforreportingsys- tematicreviews andmeta-analysesof studiesthatevaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.

[5]Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Elbourne D, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting paral- lel group randomised trials. Int J Surg 2012;10:28—55, http://dx.doi.org/10.1016/j.ijsu.2011.10.001[Epub2011Oct 12]https://www.ncbi.nlm.nih.gov/pubmed/22036893.

[6]Petrisor BA, Keating J, Schemitsch E. Grading the evidence: Levels of evidence and grades of recommen- dation. Injury 2006;37:321—7, http://dx.doi.org/10.1016/

j.injury.2006.02.001.

[7]Lin C-S, Albersen M, Xin Z, Namiki M, Muller D, Lue TF.

Phosphodiesterase-5 expression and function in the lower urinary tract: a critical review. Urology 2013;81:480—7, http://dx.doi.org/10.1016/j.urology.2012.11.028.

[8]Uckert S, Oelke M, Stief CG, Andersson K-E, Jonas U, Hedlund P. Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 2006;49:740—5, http://dx.doi.org/

10.1016/j.eururo.2005.12.050.

[9]Zenzmaier C, Sampson N, Pernkopf D, Plas E, Unter- gasser G, Berger P. Attenuated proliferation and trans- differentiationofprostatic stromal cells indicate suitability of phosphodiesterase type 5 inhibitors for prevention and treatment of benign prostatic hyperplasia. Endocrinology 2010;151:3975—84,http://dx.doi.org/10.1210/en.2009-1411.

[10] Fibbi B, Morelli A, Vignozzi L, Filippi S, Chavalmane A, De Vita G, et al. Characterization of phosphodiesterase type 5 expression and functional activity in the humanmale lower urinary tract. JSex Med2010;7:59—69, http://dx.doi.org/10.1111/j.1743-6109.2009.01511.x.

[11] Morelli A, Sarchielli E, Comeglio P, Filippi S, Mancina R, Gacci M, et al. Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalaﬁl on prostate gland oxygenation in spon- taneously hypertensive rats. J Sex Med 2011;8:2746—60, http://dx.doi.org/10.1111/j.1743-6109.2011.02416.x.

[12] ÜckertS, Waldkirch ES,Merseburger AS, Kuczyk MA, Oelke M,HedlundP.Phosphodiesterasetype5(PDE5)isco-localized with key proteins of the nitric oxide/cyclic GMP signaling in the human prostate. World J Urol 2013;31:609—14, http://dx.doi.org/10.1007/s00345-013-1048-9.

[13] Zhang X, Zang N, Wei Y, Yin J, Teng R, Seftel A, et al.

Testosterone regulatessmooth muscle contractilepathways intheratprostate:emphasisonPDE5signaling.AmJPhysiol Endocrinol Metab 2012;302:E243—53, http://dx.doi.org/10 .1152/ajpendo.00458.2011.

[14] Booth L, Roberts JL, Cruickshanks N, Conley A, Durrant DE, Das A, et al. Phosphodiesterase 5 inhibitors enhance chemotherapy killing in gastrointestinal/genitourinary can- cercells.MolPharmacol2014;85:408—19,http://dx.doi.org/

10.1124/mol.113.090043.

[15] Liu N, Mei L, Fan X, Tang C, Ji X, Hu X, et al. Phos- phodiesterase 5/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway.

Cancer Lett 2016;378:38—50, http://dx.doi.org/10.1016/

j.canlet.2016.05.010.

[16] RigamontiN, Capuano G, Ricupito A, Jachetti E,Grioni M, Generoso L, et al. Modulators of arginine metabolism do notimpact on peripheral T-cell tolerance and disease progression in a model of spontaneous prostate cancer. Clin

Cancer Res Off J Am Assoc Cancer Res 2011;17:1012—23, http://dx.doi.org/10.1158/1078-0432.CCR-10-2547.

[17]Zhu B, Vemavarapu L, Thompson WJ, Strada SJ. Suppres- sion of cyclic GMP-speciﬁc phosphodiesterase 5 promotes apoptosis and inhibitsgrowthin HT29cells.J CellBiochem 2005;94:336—50,http://dx.doi.org/10.1002/jcb.20286.

[18]Hamilton TK, Hu N, Kolomitro K, Bell EN, Maurice DH, Graham CH, et al. Potential therapeutic appli- cations of phosphodiesterase inhibition in prostate cancer. World J Urol 2013;31:325—30, http://dx.doi.org/

10.1007/s00345-012-0848-7.

[19]Qian C-N, Takahashi M, Kahnoski RJ, Teh BT. Effect of sildenaﬁl citrate on an orthotopic prostate cancer growth and metastasis model. J Urol 2003;170:994—7, http://dx.doi.org/10.1097/01.ju.0000080321.99119.df.

[20]GoluboffET,ShabsighA,SaidiJA,WeinsteinIB,MitraN,Heit- janD,etal.Exisulind(sulindacsulfone)suppressesgrowthof humanprostatecancerina nudemousexenograftmodelby increasingapoptosis.Urology1999;53:440—5.

[21]GoluboffET,PragerD,RukstalisD,GiantonioB,MadorskyM, BarkenI,etal.Safetyandefﬁcacyofexisulindfortreatment ofrecurrentprostatecancerafterradicalprostatectomy.JUrol 2001;166:882—6.

[22]Narayanan BA, Reddy BS, Bosland MC, Nargi D, Horton L, RandolphC,etal.Exisulindincombinationwithcelecoxibmod- ulates epidermal growth factor receptor,cyclooxygenase-2, andcyclinD1againstprostatecarcinogenesis:invivoevidence.

ClinCancerResOffJAmAssocCancerRes2007;13:5965—73, http://dx.doi.org/10.1158/1078-0432.CCR-07-0744.

[23]Seraﬁni P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenousantitumorimmunitybyreducingmyeloid-derived suppressor cell function. J Exp Med 2006;203:2691—702, http://dx.doi.org/10.1084/jem.20061104.

[24]Das A, Durrant D, Mitchell C, Mayton E, Hoke NN, Sal- loumFN,etal.Sildenaﬁlincreaseschemotherapeuticefﬁcacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc Natl Acad Sci U S A 2010;107:18202—7, http://dx.doi.org/10.1073/pnas.1006965107.

[25]Das A, Durrant D, Mitchell C, Dent P, Batra SK, Kukreja RC. Sildenaﬁl (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95. Oncotarget 2016;7:4399—413, http://dx.doi.org/

10.18632/oncotarget.6749.

[26]Chavez AH, Scott Cofﬁeld K, Hasan Rajab M, Jo C. Inci- dence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors:

retrospective analysis. Asian J Androl 2013;15:246—8, http://dx.doi.org/10.1038/aja.2012.162.

[27]Leitzmann MF, Platz EA, Stampfer MJ, Willett WC, Gio- vannucci E. Ejaculation frequency and subsequent risk of prostate cancer. JAMA 2004;291:1578—86, http://dx.doi.org/10.1001/jama.291.13.1578.

[28]Machen GL, Rajab MH, Pruszynski J, Cofﬁeld KS. Phospho- diesterase type 5 inhibitors usage and prostate cancer: a match-paired analysis. Transl Androl Urol 2017;6:879—82, http://dx.doi.org/10.21037/tau.2017.06.02.

[29]Jamnagerwalla J,HowardLE,VidalAC,MoreiraDM, Castro- Santamaria R, Andriole GL,et al. The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer:

Results from the REDUCE Study. J Urol 2016;196:715—20, http://dx.doi.org/10.1016/j.juro.2016.03.172.

[30]Michl U, Molfenter F, Graefen M, Tennstedt P, Ahyai S, Beyer B, et al. Use of phosphodiesterase type 5 inhibitors may adversely impact biochemical recurrence after radical prostatectomy. J Urol 2015;193:479—83, http://dx.doi.org/10.1016/j.juro.2014.08.111.

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[31]Gallina A, Bianchi M, Gandaglia G, Cucchiara V, Suardi N, Montorsi F, et al. A Detailed Analysis of the Associ- ation Between Postoperative Phosphodiesterase Type 5 Inhibitor Use and the Risk of Biochemical Recurrence After Radical Prostatectomy. Eur Urol 2015;68:750—3, http://dx.doi.org/10.1016/j.eururo.2015.02.002.

[32]Jo JK, Kim K, Lee SE, Lee JK, Byun S-S, Hong SK.

Phosphodiesterase type 5 inhibitor use following radical

prostatectomy is not associated with an increased risk of biochemical recurrence. Ann Surg Oncol 2016;23:1760—7, http://dx.doi.org/10.1245/s10434-015-5059-1.

[33]Loeb S, Folkvaljon Y, Robinson D, Schlomm T, Garmo H, Stattin P. Phosphodiesterase type 5 inhibitor use and disease recurrence after prostate cancer treatment. Eur Urol 2016;70:824—8, http://dx.doi.org/10.

1016/j.eururo.2015.12.013.