Phosphodiesterase-5 inhibitors (PDE5Is) represent a group of drugs that are registered for the treatment of erectile dysfunctions predominantly, but recently also for treatment of pulmonary hypertension and benign prostatic hypertrophy. However, more and more research deals with possible antitumor potential of PDE5Is in different types of cancers, including prostate cancer. Prostate cancer represents the one of the most common carcinoma in the male population, whose incidence is continuously increasing. Early detection combined with radical prostatectomy increases the survival rate, but also it is necessary to keep in mind the quality of life of patients undergoing prostatectomy in light of bladder control and erectile function. Authors of various clinical studies presented the results that often lead to totally opposing conclusions. For example, Chavez and colleagues have shown that use of PDE5Is in men with erectile dysfunction decreases the risk of developing prostate cancer, while, on the other hand, Michl and colleagues pointed out the adversely effect of PDE5Is on biochemical recurrence after bilateral nerve sparing radical prostatectomy. In that sense, the aim of this review was to present as many as possible of existing results dealing with of action of PDE5Is in the field of prostatic carcinoma. Taking into account all presented data, it can be concluded that eff ect of PDE5Is on formation, development and outcome of treatment in patients with prostate carcinoma is very intriguing question, whose response requires additional both experimental and clinical research.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Boolell M Allen MJ Ballard SA Gepi-Attee S Muirhead GJ Naylor AM Osterloh IH Gingell C. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996;8(2):47-52.
2. Boolell M Gepi-Attee S Gingell JC Allen MJ. Sildenafil a novel effective oral therapy for male erectile dysfunction. Br J Urol. 1996;78(2):257-61.
3. Goldstein I Lue TF Padma-Nathan H Rosen RC Steers WD Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998; 338(20): 1397-404.
4. FDA approves oral therapy for erectile dysfunction. Am J Health Syst Pharm. 1998;55(10):981-984
5. Hellstrom WJ Gittelman M Karlin G Segerson T Thibonnier M Taylor T Padma-Nathan H; Vardenafil Study Group. Sustained efficacy and tolerability of vardenafil a highly potent selective phosphodiesterase type 5 inhibitor in men with erectile dysfunction: results of a randomized double-blind 26-week placebo-controlled pivotal trial. Urology. 2003;61(4 Suppl 1):8-14.
6. Govier F Potempa AJ Kaufman J Denne J Kovalenko P Ahuja S. A multicenter randomized double-blind crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther. 2003 Nov;25(11):2709-23.
7. Limin M Johnsen N Hellstrom WJ. Avanafil a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Expert Opin Investig Drugs. 2010;19(11):1427-37.
8. Mendes GD dos Santos Filho HO dos Santos Pereira A Mendes FD Ilha JO Alkharfy KM De Nucci G. A Phase I clinical trial of lodenafil carbonate a new phosphodiesterase Type 5 (PDE5) inhibitor in healthy male volunteers. Int J Clin Pharmacol Ther. 2012;50(12):896-906.
9. Moon KH Kim SW Moon du G Kim JJ Park NC Lee SW Paick JS Ahn TY Chung WS Min KS Park JK Yang DY Shin HS Park K. A Phase 3 Study to Evaluate the 1-Year Efficacy and Safety of Udenafil 75 mg Once Daily in Patients With Erectile Dysfunction. J Sex Med. 2016;13(8):1263-9.
10. Du W Li J Fan N Shang P Wang Z Ding H. Efficacy and safety of mirodenafil for patients with erectile dysfunction: a meta-analysis of three multicenter randomized double-blind placebo-controlled clinical trials. Aging Male. 2014;17(2):107-11.
11. Hwang IC Kim YJ Park JB Yoon YE Lee SP Kim HK Cho GY Sohn DW. Pulmonary hemodynamics and effects of phosphodiesterase type 5 inhibition in heart failure: a meta-analysis of randomized trials. BMC Cardiovasc Disord. 2017;17(1):150.
12. Anderson SG Hutchings DC Woodward M Rahimi K Rutter MK Kirby M Hackett G Trafford AW Heald AH. Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality. Heart. 2016;102(21):1750-1756.
13. Wang L Chopp M Szalad A Jia L Lu X Lu M Zhang L Zhang Y Zhang R Zhang ZG. Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice. PLoS One. 2015;10(2):e0118134.
14. Wang L Chopp M Szalad A Liu Z Bolz M Alvarez FM Lu M Zhang L Cui Y Zhang RL Zhang ZG. Phosphodiesterase- 5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience. 2011; 193: 399-410.
15. El-Mahdy NA El-Sayad Mel-S El-Kadem AH. Combination of telmisartan with sildenafil ameliorate progression of diabetic nephropathy in streptozotocininduced diabetic model. Biomed Pharmacother. 2016; 81: 136-44.
16. Afsar B Ortiz A Covic A Gaipov A Esen T Goldsmith D Kanbay M. Phosphodiesterase type 5 inhibitors and kidney disease. Int Urol Nephrol. 2015; 47(9): 1521-8.
17. Zhang R Wang Y Zhang L Zhang Z Tsang W Lu M Zhang L Chopp M. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002; 33(11): 2675-80.
18. Ding G Jiang Q Li L Zhang L Zhang Z Lu M Li Q Gu S Ewing J Chopp M. Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats. Stroke. 2011; 42(12): 3537-41.
19. Zhang L Zhang Z Zhang RL Cui Y LaPointe MC Silver B Chopp M. Tadalafil a long-acting type 5 phosphodiesterase isoenzyme inhibitor improves neurological functional recovery in a rat model of embolic stroke. Brain Res. 2006; 1118(1): 192-8.
20. Ölmestig JNE Marlet IR Hainsworth AH Kruuse C. Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies. Cell Signal. 2017;38:39-48.
21. Ghofrani HA Wiedemann R Rose F Schermuly RT Olschewski H Weissmann N Gunther A Walmrath D Seeger W Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002; 360(9337): 895-900.
22. Kumazoe M Sugihara K Tsukamoto S Huang Y Tsurudome Y Suzuki T Suemasu Y Ueda N Yamashita S Kim Y Yamada K Tachibana H. 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. J Clin Invest. 2013;123(2):787-99.
23. Marques JG Gaspar VM Markl D Costa EC Gallardo E Correia IJ. Co-delivery of Sildenafil (Viagra(®)) and Crizotinib for synergistic and improved anti-tumoral therapy. Pharm Res. 2014; 31(9): 2516-28.
24. Bender AT Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006 Sep;58(3):488-520.
25. Yoo TH Pedigo CE Guzman J Correa-Medina M Wei C Villarreal R Mitrofanova A Leclercq F Faul C Li J Kretzler M Nelson RG Lehto M Forsblom C Groop PH Reiser J Burke GW Fornoni A Merscher S. Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. J Am Soc Nephrol. 2015; 26(1): 133-47.
26. Amirjanians M Egemnazarov B Sydykov A Kojonazarov B Brandes R Luitel H Pradhan K Stasch JP Redlich G Weissmann N Grimminger F Seeger W Ghofrani H Schermuly R. Chronic intratracheal application of the soluble guanylyl cyclase stimulator BAY 41-8543 ameliorates experimental pulmonary hypertension. Oncotarget. 2017; 8(18): 29613-29624.
27. Lee DI Zhu G Sasaki T Cho GS Hamdani N Holewinski R Jo SH Danner T Zhang M Rainer PP Bedja D Kirk JA Ranek MJ Dostmann WR Kwon C Margulies KB Van Eyk JE Paulus WJ Takimoto E Kass DA. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature. 2015; 519(7544): 472-6.
28. Matsui H Sopko NA Hannan JL Bivalacqua TJ. Pathophysiology of erectile dysfunction. Curr Drug Targets. 2015; 16(5): 411-9.
29. Movsesian MA Kukreja RC. Phosphodiesterase inhibition in heart failure. Handb Exp Pharmacol. 2011; (204): 237-49.
30. Bender AT Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006; 58(3): 488-520.
32. Boswell-Smith V Spina D Page CP. Phosphodiesterase inhibitors. Br J Pharmacol. 2006; 147 Suppl 1: S252-7.
33. Francis SH Blount MA Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev. 2011; 91(2): 651-90.
34. Ahmad F Murata T Shimizu K Degerman E Maurice D Manganiello V. Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets. Oral Dis. 2015; 21(1): e25-50.
35. Coquil JF Franks DJ Wells JN Dupuis M Hamet P. Characteristics of a new binding protein distinct from the kinase for guanosine 3’:5’-monophosphate in rat platelets. Biochim Biophys Acta. 1980; 631(1): 148-65.
36. Francis SH Lincoln TM Corbin JD. Characterization of a novel cGMP binding protein from rat lung. J Biol Chem. 1980; 255(2): 620-6.
37. Kotera J Fujishige K Omori K. Immunohistochemical localization of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in rat tissues. J Histochem Cytochem. 2000; 48(5): 685-93.
38. Shimizu-Albergine M Rybalkin SD Rybalkina IG Feil R Wolfsgruber W Hofmann F Beavo JA. Individual cerebellar Purkinje cells express different cGMP phosphodiesterases (PDEs): in vivo phosphorylation of cGMP-specific PDE (PDE5) as an indicator of cGMPdependent protein kinase (PKG) activation. J Neurosci. 2003; 23(16): 6452-9.
39. Akand M Gencer E Yaman Ö Erişgen G Tekin D Özdiler E. Effect of sildenafil on platelet function and platelet cGMP of patients with erectile dysfunction. Andrologia. 2015; 47(10): 1098-102.
40. Sasser JM Ni XP Humphreys MH Baylis C. Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to a nitric oxide donor in the pregnant rat. Am J Physiol Renal Physiol. 2010; 299(4): F810-4.
41. Santos AI Carreira BP Nobre RJ Carvalho CM Araújo IM. Stimulation of neural stem cell proliferation by inhibition of phosphodiesterase 5. Stem Cells Int. 2014; 2014: 878397.
42. Peixoto CA Nunes AK Garcia-Osta A. Phosphodiesterase-5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation Neurodegeneration and Cognition. Mediators Inflamm. 2015; 2015: 940207.
43. Murthy KS. Activation of phosphodiesterase 5 and inhibition of guanylate cyclase by cGMP-dependent protein kinase in smooth muscle. Biochem J. 2001; 360(Pt 1): 199-208.
44. Dhooghe B Noël S Bouzin C Behets-Wydemans G Leal T. Correction of chloride transport and mislocalization of CFTR protein by vardenafil in the gastrointestinal tract of cystic fibrosis mice. PLoS One. 2013; 8(10): e77314.
45. Turko IV Francis SH Corbin JD. Studies of the molecular mechanism of discrimination between cGMP and cAMP in the allosteric sites of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J Biol Chem. 1999; 274(41): 29038-41.
46. Kotera J Francis SH Grimes KA Rouse A Blount MA Corbin JD. Allosteric sites of phosphodiesterase-5 sequester cyclic GMP. Front Biosci. 2004; 9: 378-86.
47. Corbin JD Turko IV Beasley A Francis SH. Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem. 2000; 267(9): 2760-7.
48. Francis SH Bessay EP Kotera J Grimes KA Liu L Thompson WJ Corbin JD. Phosphorylation of isolated human phosphodiesterase-5 regulatory domain induces an apparent conformational change and increases cGMP binding affinity. J Biol Chem. 2002; 277(49): 47581-7.
49. Al-Shboul O Mahavadi S Sriwai W Grider JR Murthy KS. Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle. Am J Physiol Gastrointest Liver Physiol. 2013; 305(4): G314-24.
50. Castro LR Schittl J Fischmeister R. Feedback control through cGMP-dependent protein kinase contributes to differential regulation and compartmentation of cGMP in rat cardiac myocytes. Circ Res. 2010; 107(10): 1232-40.
51. Mullershausen F Lange A Mergia E Friebe A Koesling D. Desensitization of NO/cGMP signaling in smooth muscle: blood vessels versus airways. Mol Pharmacol. 2006; 69(6): 1969-74.
52. Stegbauer J Friedrich S Potthoff SA Broekmans K Cortese-Krott MM Quack I Rump LC Koesling D Mergia E. Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension. PLoS One. 2013; 8(11): e80674.
53. Lin CS. Phosphodiesterase type 5 regulation in the penile corpora cavernosa. J Sex Med. 2009; 6 Suppl 3: 203-9.
54. Murthy KS. Contractile agonists attenuate cGMP levels by stimulating phosphorylation of cGMP-specific PDE5; an effect mediated by RhoA/PKC-dependent inhibition of protein phosphatase 1. Br J Pharmacol. 2008; 153(6): 1214-24.
55. Rybalkin SD Rybalkina IG Feil R Hofmann F Beavo JA. Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem. 2002; 277(5): 3310-7.
56. Frame MJ Tate R Adams DR Morgan KM Houslay MD Vandenabeele P Pyne NJ. Interaction of caspase-3 with the cyclic GMP binding cyclic GMP specific phosphodiesterase (PDE5a1). Eur J Biochem. 2003; 270(5): 962-70.
57. Lin CS. Tissue expression distribution and regulation of PDE5. Int J Impot Res. 2004; 16 Suppl 1: S8-S10.
58. Reffelmann T Kloner RA. Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation. 2003; 108(2): 239-44.
59. Sopory S Kaur T Visweswariah SS. The cGMP-binding cGMP-specific phosphodiesterase (PDE5): intestinal cell expression regulation and role in fluid secretion. Cell Signal. 2004; 16(6): 681-92
60. Scipioni A Giorgi M Nuccetelli V Stefanini S. Immunohistochemical localisation of PDE5 in rat lung during pre- and postnatal development. J Biomed Biotechnol. 2009; 2009: 932961.
61. Kedia GT Ückert S Oelke M Sonnenberg JE Sohn M Kuczyk MA Hedlund P. Expression and distribution of phosphodiesterase isoenzymes in the human male urethra. Urology. 2015; 85(4): 964.e1-6.
62. Fibbi B Morelli A Vignozzi L Filippi S Chavalmane A De Vita G Marini M Gacci M Vannelli GB Sandner P Maggi M. Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. J Sex Med. 2010; 7(1 Pt 1): 59-69.
63. Zhu B Vemavarapu L Thompson WJ Strada SJ. Suppression of cyclic GMP-specific phosphodiesterase 5 promotes apoptosis and inhibits growth in HT29 cells. J Cell Biochem. 2005; 94(2): 336-50.
64. Li Q Shu Y. Pharmacological modulation of cytotoxicity and cellular uptake of anti-cancer drugs by PDE5 inhibitors in lung cancer cells. Pharm Res. 2014; 31(1): 86-96.
65. Catalano S Campana A Giordano C Győrffy B Tarallo R Rinaldi A Bruno G Ferraro A Romeo F Lanzino M Naro F Bonofiglio D Andò S Barone I. Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy. Clin Cancer Res. 2016; 22(9): 2271-82.
66. Hamilton TK Hu N Kolomitro K Bell EN Maurice DH Graham CH Siemens DR. Potential therapeutic applications of phosphodiesterase inhibition in prostate cancer. World J Urol. 2013; 31(2): 325-30.
67. Piazza GA Thompson WJ Pamukcu R Alila HW Whitehead CM Liu L Fetter JR Gresh WE Jr Klein-Szanto AJ Farnell DR Eto I Grubbs CJ. Exisulind a novel proapoptotic drug inhibits rat urinary bladder tumorigenesis. Cancer Res. 2001; 61(10): 3961-8.
68. Karami-Tehrani F Moeinifard M Aghaei M Atri M. Evaluation of PDE5 and PDE9 expression in benign and malignant breast tumors. Arch Med Res. 2012; 43(6): 470-5.
69. Booth L Roberts JL Cruickshanks N Conley A Durrant DE Das A Fisher PB Kukreja RC Grant S Poklepovic A Dent P. Phosphodiesterase 5 inhibitors enhance chemotherapy killing in gastrointestinal/genitourinary cancer cells. Mol Pharmacol. 2014; 85(3): 408-19.
70. Marino N Collins JW Shen C Caplen NJ Merchant AS Gökmen-Polar Y Goswami CP Hoshino T Qian Y Sledge GW Jr Steeg PS. Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines. Clin Exp Metastasis. 2014; 31(7): 771-86.
71. Ryu YK Lee MH Lee J Lee JW Jang SJ Kang JH Moon EY. γ-Irradiated cancer cells promote tumor growth by activation of Toll-like receptor 1-mediated inducible nitric oxide synthase in macrophages. J Leukoc Biol. 2015; 97(4): 711-21.
72. Li L Zhu L Hao B Gao W Wang Q Li K Wang M Huang M Liu Z Yang Q Li X Zhong Z Huang W Xiao G Xu Y Yao K Liu Q. iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer. Oncotarget. 2017; 8(20): 33047-33063.
73. Basudhar D Somasundaram V de Oliveira GA Kesarwala A Heinecke JL Cheng RY Glynn SA Ambs S Wink DA Ridnour LA. Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression. Antioxid Redox Signal. 2017; 26(18): 1044-1058.
74. Liu Y Wang Y Hu Y Ge S Li K Wang S Li L. The apoptotic inducible effects of salicylic acid on hepatoma cell line: relationship with nitric oxide signaling. J Cell Commun Signal. 2017. doi: 10.1007/s12079-017-0380-z.
75. Günzle J Osterberg N Saavedra JE Weyerbrock A. Nitric oxide released from JS-K induces cell death by mitotic catastrophe as part of necrosis in glioblastoma multiforme. Cell Death Dis. 2016; 7(9): e2349.
76. Burke AJ Sullivan FJ Giles FJ Glynn SA. The yin and yang of nitric oxide in cancer progression. Carcinogenesis. 2013; 34(3): 503-12.
77. Cheng H Wang L Mollica M Re AT Wu S Zuo L. Nitric oxide in cancer metastasis. Cancer Lett. 2014; 353(1): 1-7.
78. Bian K Murad F. Nitric oxide (NO)--biogeneration regulation and relevance to human diseases. Front Biosci. 2003; 8: d264-78.
79. Bian K Ghassemi F Sotolongo A Siu A Shauger L Kots A Murad F. NOS-2 signaling and cancer therapy. IUBMB Life. 2012; 64(8): 676-83.
80. Chang WL Masih S Thadi A Patwa V Joshi A Cooper HS Palejwala VA Clapper ML Shailubhai K. Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc(+/Min-FCCC) mice. World J Gastrointest Pharmacol Ther. 2017;8(1):47-59.
81. Cesarini V Martini M Vitiani LR Gravina GL Di Agostino S Graziani G D’Alessandris QG Pallini R Larocca LM Rossi P Jannini EA Dolci S. Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. Oncotarget. 2017;8(8):13223-13239.
82. Bian K Murad F. sGC-cGMP signaling: target for anticancer therapy. Adv Exp Med Biol. 2014;814:5-13.
83. Crocetti E. (2015). Centre for Parliamentary Studies. Retrieved November 15th 2017 from https://ec.europa.eu/jrc/en/publication/epidemiology-prostate-cancer-europe
84. Hirik E Bozkurt A Karabakan M Onuk Ö Balcı MB Aydın M Çakan M Nuhoglu B. Results of tadalafil treatment in patients following an open nerve-sparing radical prostatectomy. Arch Ital Urol Androl. 2016; 88(1): 4-6.
85. Liu N Mei L Fan X Tang C Ji X Hu X Shi W Qian Y Hussain M Wu J Wang C Lin S Wu X. Phosphodiesterase 5/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway. Cancer Lett. 2016; 378(1): 38-50.
86. 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(4): 4399-413.
87. Koka S Das A Zhu SG Durrant D Xi L Kukreja RC. Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. J Pharmacol Exp Ther. 2010; 334(3): 1023-30.
88. Ammirante M Shalapour S Kang Y Jamieson CA Karin M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc Natl Acad Sci U S A. 2014; 111(41):14776-81.
89. Chavez AH Scott Coffield K Hasan Rajab M Jo C. Incidence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors: retrospective analysis. Asian J Androl. 2013; 15(2): 246-8.
90. Jamnagerwalla J Howard LE Vidal AC Moreira DM Castro-Santamaria R Andriole GL Freedland SJ. The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study. J Urol. 2016; 196(3): 715-20.
91. Jo JK Kim K Lee SE Lee JK Byun SS 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(5): 1760-7.
92. Michl U Molfenter F Graefen M Tennstedt P Ahyai S Beyer B Budäus L Haese A Heinzer H Oh SJ Salomon G Schlomm T Steuber T Thederan I Huland H Tilki D. Use of phosphodiesterase type 5 inhibitors may adversely impact biochemical recurrence after radical prostatectomy. J Urol. 2015; 193(2): 479-83.
93. Zhang R Wang Y Zhang L Zhang Z Tsang W Lu M Zhang L Chopp M. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002; 33(11): 2675-80.
94. Koneru S Varma Penumathsa S Thirunavukkarasu M Vidavalur R Zhan L Singal PK Engelman RM Das DK Maulik N. Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1. J Cell Mol Med. 2008; 12(6B): 2651-64.
95. Magnon C Hall SJ Lin J Xue X Gerber L Freedland SJ Frenette PS. Autonomic nerve development contributes to prostate cancer progression. Science. 2013; 341(6142): 1236361.
96. Ronca R Benkheil M Mitola S Struyf S Liekens S. Tumor angiogenesis revisited: Regulators and clinical implications. Med Res Rev. 2017. doi: 10.1002/med.21452.
97. El-Naa MM Othman M Younes S. Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis. Drug Des Devel Ther. 2016; 10: 3661-3672.
98. Bora GS Gupta VG Mavuduru RS. Re: Use of Phosphodiesterase Type 5 Inhibitors May Adversely Impact Biochemical Recurrence after Radical Prostatectomy: U. Michl F. Molfenter M. Graefen P. Tennstedt S. Ahyai B. Beyer L. Budäus A. Haese H. Heinzer S. J. Oh G. Salomon T. Schlomm T. Steuber I. Thederan H. Huland and D. Tilki J Urol 2015; 193: 479-483. J Urol. 2016; 195(3): 804;
99. Gallina A Bianchi M Gandaglia G Cucchiara V Suardi N Montorsi F Briganti A. A Detailed Analysis of the Association Between Postoperative Phosphodiesterase Type 5 Inhibitor Use and the Risk of Biochemical Recurrence After Radical Prostatectomy. Eur Urol. 2015; 68(5): 750-3.