Measurement of PDE5 concentration in human serum: proof-of-concept and validation of methodology in control and prostate cancer patients.
Benign prostatic hyperplasia
Novel markers of disease
Phosphodiesterase type 5
Prostate cancer
Journal
Journal of endocrinological investigation
ISSN: 1720-8386
Titre abrégé: J Endocrinol Invest
Pays: Italy
ID NLM: 7806594
Informations de publication
Date de publication:
01 Oct 2024
01 Oct 2024
Historique:
received:
14
05
2024
accepted:
29
06
2024
medline:
1
10
2024
pubmed:
1
10
2024
entrez:
1
10
2024
Statut:
aheadofprint
Résumé
We aimed to investigate if the type 5 phosphodiesterase (PDE5), an enzyme with cardinal biological functions in sexual and cardiovascular health, can be detected and quantited in human serum. Blood samples were collected from control male and female subjects. PDE5 levels were measured by a specific ELISA kit. ROC curves weighted for age and serum levels of PSA (male subjects), or age (female subjects) were used to identify the predictive ability in the detection of PCa. Sensitivity, specificity, PPV and NPV values were determined for cut-off value determined during ROC curve analysis. 41 control male subjects, 18 control female subjects, and 55 consecutive subjects, of which 25 were affected by benign prostatic hypertrophy (BPH) and 30 with histologically confirmed prostate cancer (PCa), were studied. PDE5 serum levels were detectable in all subjects (range: 5 to 65 ng/ml). Analysis by MANCOVA identified a significant difference in serum PDE5 between control subjects or hyperplasia patients and PCa patients. Marginal means of serum PDE5 concentrations showed a significant difference (p < 0.001). The ROC curve demonstrated that PDE5 serum levels can predict men with or without PCa, with 0.806 AUC value (p < 0.0001). Using a 12.705 ng/ml PDE5 serum cut-off yielded sensitivity, specificity, PPV, and NPV of 83.3%, 77.27%, 62.5%, and 91.1% in detecting men with histologically proven PCa, respectively. We demonstrated, for the first time, that PDE5 levels can be detected in human sera and that PCa patients have significantly higher PDE5 concentration compared to BPH patients or male and female controls. While serum PDE5 level measurement may open new research avenues, the clinical relevance of PDE5 levels in PCa patients deserves further investigation.
Identifiants
pubmed: 39352630
doi: 10.1007/s40618-024-02428-w
pii: 10.1007/s40618-024-02428-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Carosa E, Rossi S, Giansante N, Gravina GL, Castri A, Dolci S et al (2009) The ontogenetic expression pattern of type 5 phosphodiesterase correlates with androgen receptor expression in rat corpora cavernosa. J Sex Med 6(2):388–396. https://doi.org/10.1111/j.1743-6109.2008.01091.x
doi: 10.1111/j.1743-6109.2008.01091.x
pubmed: 19138372
Dolci S, Belmonte A, Santone R, Giorgi M, Pellegrini M, Carosa E, Piccione E, Lenzi A, Jannini EA (2006) Subcellular localization and regulation of type-1 C and type-5 phosphodiesterases. Biochem Biophys Res Commun 341(3):837–846. https://doi.org/10.1016/j.bbrc.2006.01.035
doi: 10.1016/j.bbrc.2006.01.035
pubmed: 16455054
Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M et al (2004) Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 145(5):2253–2263. https://doi.org/10.1210/en.2003-1699
doi: 10.1210/en.2003-1699
pubmed: 14764637
Bisegna C, Gravina GL, Pierconti F, Martini M, Larocca L, Rossi P et al (2020) Regulation of PDE5 expression in normal prostate, benign prostatic hyperplasia, and adenocarcinoma. Andrology 8(2):427–433. https://doi.org/10.1111/andr.12695
doi: 10.1111/andr.12695
pubmed: 31433119
Yetik-Anacak G, Sorrentino R, Linder AE, Murat N (2015) Gas what: NO is not the only answer to sexual function. Br J Pharmacol 172(6):1434–1454. https://doi.org/10.1111/bph.12700
doi: 10.1111/bph.12700
pubmed: 24661203
Corbin JD, Francis SH (1999) Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 274(20):13729–13732. https://doi.org/10.1074/jbc.274.20.13729
doi: 10.1074/jbc.274.20.13729
pubmed: 10318772
Uckert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P (2006) Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 49(4):740–745. https://doi.org/10.1016/j.eururo.2005.12.050
doi: 10.1016/j.eururo.2005.12.050
pubmed: 16460876
Wang L, Zhang X, Wang G, Visweswariah SS, Lin G, Xin Z, Lue TF, Lin CS (2015) Lobe-specific expression of phosphodiesterase 5 in rat prostate. Urology 85(3):703–e707. https://doi.org/10.1016/j.urology.2014.12.005
doi: 10.1016/j.urology.2014.12.005
Joe AK, Liu H, Xiao D, Soh JW, Pinto JT, Beer DG, Piazza GA, Thompson WJ, Weinstein IB (2003) Exisulind and CP248 induce growth inhibition and apoptosis in human esophageal adenocarcinoma and squamous carcinoma cells. J Exp Ther Oncol 3(2):83–94. https://doi.org/10.1046/j.1359-4117.2003.01076.x
doi: 10.1046/j.1359-4117.2003.01076.x
pubmed: 12822514
Piazza GA, Thompson WJ, Pamukcu R, Alila HW, Whitehead CM, Liu L et al (2001) Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis. Cancer Res 61(10):3961–3968
pubmed: 11358813
Lim JT, Piazza GA, Pamukcu R, Thompson WJ, Weinstein IB (2003) Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells. Clin Cancer Res 9(13):4972–4982
pubmed: 14581372
Whitehead CM, Earle KA, Fetter J, Xu S, Hartman T, Chan DC et al (2003) Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. Mol Cancer Ther 2(5):479–488
pubmed: 12748310
Cesarini V, Martini M, Vitiani LR, Gravina GL, Di Agostino S, Graziani G et al (2017) Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. Oncotarget 8(8):13223–13239. https://doi.org/10.18632/oncotarget.14656
doi: 10.18632/oncotarget.14656
pubmed: 28099939
pmcid: 5355091
Huang W, Sundquist J, Sundquist K, Ji J (2020) Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer. Nat Commun 11(1):3191. https://doi.org/10.1038/s41467-020-17028-4
doi: 10.1038/s41467-020-17028-4
pubmed: 32581298
pmcid: 7314744
Carosa E, Castri A, Forcella C, Sebastiani G, Di Sante S, Gravina GL et al (2014) Platelet-derived growth factor regulation of type-5 phosphodiesterase in human and rat penile smooth muscle cells. J Sex Med 11(7):1675–1684. https://doi.org/10.1111/jsm.12568
doi: 10.1111/jsm.12568
pubmed: 24836457
https://seer.cancer.gov/statfacts/html/prost.html
EAU - EANM - ESTRO - ESUR - ISUP - SIOG Guidelines on Prostate Cancer (2024) EAU Guidelines Office. https://uroweb.org/guidelines/prostate-cancer . Accessed April 29 2024
Sandhu JS, Bixler BR, Dahm P, Goueli R, Kirkby E, Stoffel JT, Wilt TJ (2024) Management of lower urinary tract symptoms attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023. J Urol 211(1):11–19. https://doi.org/10.1097/JU.0000000000003698
doi: 10.1097/JU.0000000000003698
pubmed: 37706750
Isidori AM, Aversa A, Calogero A, Ferlin A, Francavilla S, Lanfranco F et al (2022) Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian society of andrology and sexual medicine (SIAMS) and the Italian Society of Endocrinology (SIE). J Endocrinol Investig 45(12):2385–2403. https://doi.org/10.1007/s40618-022-01859-7
doi: 10.1007/s40618-022-01859-7
Lin C-S, Chow S, Lau A, Tu R, Lue TF (2001) Regulation of human PDE5A2 intronic promoter by cAMP and cGMP: identification of a critical Sp1-Binding site. Biochem Biophys Res Commun 280(3):693–699. https://doi.org/10.1006/bbrc.2000.4221
doi: 10.1006/bbrc.2000.4221
pubmed: 11162576
Lin G, Xin Z-C, Lue TF, Lin C-S (2003) Up and down-regulation of Phosphodiesterase-5 as related to Tachyphylaxis and Priapism. J Urol 170(2S). https://doi.org/10.1097/01.ju.0000075500.11519.e8
Gonzalez RR, Kaplan SA (2006) Tadalafil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. Expert Opin Drug Metab Toxicol 2(4):609–617. https://doi.org/10.1517/17425255.2.4.609
doi: 10.1517/17425255.2.4.609
pubmed: 16859408
Djavan B, Zlotta A, Remzi M, Ghawidel K, Basharkhah A, Schulman CC, Marberger M (2000) Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men. J Urol 163(4):1144–1148 discussion 1148–1149
doi: 10.1016/S0022-5347(05)67711-7
pubmed: 10737484
Marks LS, Fradet Y, Deras IL, Blase A, Mathis J, Aubin SM et al (2007) PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology 69(3):532–535. https://doi.org/10.1016/j.urology.2006.12.014
doi: 10.1016/j.urology.2006.12.014
pubmed: 17382159
Aubin SM, Reid J, Sarno MJ, Blase A, Aussie J, Rittenhouse H, Rittmaster R, Andriole GL, Groskopf J (2010) PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. J Urol 184(5):1947–1952. https://doi.org/10.1016/j.juro.2010.06.098
doi: 10.1016/j.juro.2010.06.098
pubmed: 20850153
Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, Broyles DL et al (2010) A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 19(5):1193–1200. https://doi.org/10.1158/1055-9965.EPI-10-0007
doi: 10.1158/1055-9965.EPI-10-0007
pubmed: 20447916
pmcid: 2867076
Zhang W, Zang N, Jiang Y, Chen P, Wang X, Zhang X (2015) Upregulation of phosphodiesterase type 5 in the hyperplastic prostate. Sci Rep 5:17888. https://doi.org/10.1038/srep17888
doi: 10.1038/srep17888
pubmed: 26657792
pmcid: 4674741
Zagaja GP, Mhoon DA, Aikens JE, Brendler CB (2000) Sildenafil in the treatment of erectile dysfunction after radical prostatectomy. Urology 56(4):631–634. https://doi.org/10.1016/s0090-4295(00)00659-2
doi: 10.1016/s0090-4295(00)00659-2
pubmed: 11018620
Michl U, Molfenter F, Graefen M, Tennstedt P, Ahyai S, Beyer B et al (2015) Use of phosphodiesterase type 5 inhibitors may adversely impact biochemical recurrence after radical prostatectomy. J Urol 193(2):479–483. https://doi.org/10.1016/j.juro.2014.08.111
doi: 10.1016/j.juro.2014.08.111
pubmed: 25196656
Flores JM, Vertosick E, Jenkins LC, Cooper J, Benfante N, Sjoberg D et al (2024) Do phosphodiesterase type 5 inhibitors increase the risk of biochemical recurrence after radical prostatectomy? J Urol 211(3):400–406. https://doi.org/10.1097/JU.0000000000003823
doi: 10.1097/JU.0000000000003823
pubmed: 38194487
Burnett AL, Nehra A, Breau RH, Culkin DJ, Faraday MM, Hakim LS et al (2018) Erectile Dysfunction: AUA Guideline. J Urol 200(3):633–641. https://doi.org/10.1016/j.juro.2018.05.004
doi: 10.1016/j.juro.2018.05.004
pubmed: 29746858
Danley KT, Tan A, Catalona WJ, Leikin R, Helenowski I, Jovanovic B, Gurley M, Kuzel TM (2022) The association of phosphodiesterase-5 inhibitors with the biochemical recurrence-free and overall survival of patients with prostate cancer following radical prostatectomy. Urol Oncol 40 (2):57 e51-57 e57. https://doi.org/10.1016/j.urolonc.2021.05.031