UNIVERSITA’ DI CATANIA

1. UNIVERSITA’ DI CATANIA U.O.C UROLOGIA Direttore Prof. Giuseppe Morgia Riscontri istologici del trattamento farmacologico della flogosi Vincenzo Favilla

2. Inflammation and prostate disease

3. Inflammation and prostate disease

5. Elkahwaji JE et al Research and Report in Urology 2013

6. Although BPH and CaP form in different areas of the prostate, chronic inflammation is a common finding in benign and malignant prostate tissue. BPH CaP Flogosi De Nunzio C et al Eur Urol 2011

7. micronodular hyperplasia macroscopic nodular BPH MTOPS REDUCE Inflammation Precancerous lesions Prostate cancer ? CaP

8. Inflammation and prostate cancer

9. Inflammation and prostate cancer Promotion/progression Initiation

10. Inflammation and prostate cancer Inflammation in prostate cancer: cause or consequence ? Moreira DM et al Prostate 2015

11. Prostatic inflammation as a target for CaP prevention and treatment Phytotherapy and nutraceuticals Nonsteroidal Anti-Inflammatory Drugs Other (Vitamin D, Statin, PDE5i) Quali riscontri istologici nel trattamento della flogosi ?

12. Fitoterapici e nutraceutici Meccanismi d’azione Principi attivi • Inbizione 5 alfa-reduttasi • Alfa litica • Antiproliferativa • Anti-infiammatoria • Antiossidante • Antiestrogenica • Antiandrogenica Fitosteroli Fitoestrogeni Acidi grassi Lecitine Flavonoidi Terpeni Lignani Licopene Selenio Zinco Vit. D

13. In treated animals the stroma was less cellular and contained less inflammatory foci compared to vehicle-treated group (black stars) but showed an increase of fibrosis ( red stars) Bernichtein S et al Prostate 2015

14. Human prostatic primary cultures obtained from patients undergoing radical prostatectomy (n=40) treated with 44 and 88 μg/ml of serenoa (at 24h-48h-72 h) vs untreated In both LNCaP and PC3 tumor cell lines, serenoa significantly reduced cell growth at all time points (24, 48 and 72 hours after stimulation) when compared to untreated cells (p < 0.05). LnCaP: androgen-dependent human Prostate Cancer cell line PC3: androgen independent Silvestri I et al Journal of Inflammation 2013

15. In both LNCaP and PC3 tumor cell lines, all the inflammation-related genes (IL-6, CCL-5, CCL-2, COX-2 and iNOS) were down-regulated by serenoa when compared to untreated cells UN = untreated; LS = LSESr treated Silvestri I et al Journal of Inflammation 2013

17. SeR + Se+ Ly “ Male Sprague Dawley Rats” “ IPB indotta” • Valutare l’effetto anti-infiammatorio della combinazione Serenoa Repens + Selenium + Lycopene nei ratti con BPH indotta. • Misurazione dei livelli prostatici di COX-2, 5-LOX, iNOS, IkB-α, NF-kB e l’espressione genica del TNF-α, malondialdeide e livelli di nitriti

18. Ridurre il fenotipo pro-infiammatorio Ridurre la risposta proliferativa * * * * * * * * L’associazione SeR – Ly-Se è risultata più efficace

19. OBIETTIVO Valutare l’efficacia della combinazione SeR+ Se+ Ly nella riduzione della flogosi cronica prostatica.

22. 113 men with prostate cancer randomized to consume six cups daily for 2 mo of brewed GT, BT or water (control) prior to radical prostatectomy (RP) Tissue immunostaining of proliferation (Ki67), apoptosis (Bcl2, Bax, Tunel) and inflammation (NFkB) and oxidation (8oHdG) p= NS p= 0.013 p= NS Henning SM et al Prostate 2015

23. Henning SM et al Prostate 2015

24. Conclusions Unfortunately, scientific evidences about polyphenols should be still demonstrated and well-conducted clinical studies are needed to clarify the efficacy of these molecules on prevention of PCa Oxidative Med and Cell Long 2012

25. 60 patients with primary mHGPIN and/or ASAP receiving daily lycopene 35 mg, selenium 55mg, and GTCs 600 mg or placebo for 6 months Administration of high doses of lycopene, GTCs, and selenium in men harboring HGPIN and/or ASAP was associated with a higher incidence of PCa at re-biopsy and expression of microRNAs implicated in PCa progression at molecular analysis. Gontero P et al Prostate 2015

26. Fitoterapici e nutraceutici • Efficacia antiinfiammatoria e antiproliferativa dimostrata in studi in vitro e modelli animali • Limitate evidenze di efficacia in studi clinici, randomizzati, placebo-controllati (eterogeneità popolazioni, dosaggi, composizione, bias di arruolamento) • Possibile azione promuovente il CaP quando utilizzati ad alte dosi (SELECT trial, Gontero P et al ) • Evidenze cliniche insufficienti per raccomandarne l’uso nel CaP

27. Flogosi e Patologie Prostatiche Phytotherapy NonsteroidalAnti-InflammatoryDrugs Other (Vitamin D, statin, PDE5i)

28. X COX-1 : costitutively expressed; COX-2: inducible form (in response to inflammatory stimuli) Ishiguro H et al BioMed Res Int 2014

29. The expression of both COX-1 and COX-2 in human CaP is increased. COX-2 expression is also increased in the basal and luminal epithelial cells of PIN Kirschenbaum A et al Urology 2000

30. Wang W et al Prostate 2004

31. Tissue sections of rat prostate tumor induced byN-methyl-N-nitrosourea (MNU) plus testosterone Immunohistochemical detection of inflammation markers Macrophage density Narayanan K et al Prostate 2009

32. Effect of celecoxib on macrophage,TNFa,VEGF,iNOS,NFkBp65, and rate of apoptosis Narayanan K et al Prostate 2009

33. 10 case–control and 14 cohort studies with a total of 24,230 prostate cancer cases. The epidemiologic evidence for a protective effect of aspirin and other NSAID use against prostate cancer is suggestive but not conclusive Limits Short time exposure Disease misclassification Dose and duration of use Eterogeneity of population Mahmud SM et al Int. J. Cancer 2010

34. Antiinfiammatori non sterodei • Efficacia antiinfiammatoria e antiproliferativa dimostrata in studi in vitro e modelli animali • Limitate evidenze di efficacia in studi clinici, randomizzati, placebo-controllati • Possibile azione protettiva sul CaP (metanalisi)

35. Flogosi e Patologie Prostatiche Phytotherapy NonsteroidalAnti-InflammatoryDrugs Other (Vitamin D, statin, PDE5i)

36. Vitamina D (calcitriolo) The prostate is a target organ of VDR agonists and represents an extrarenal synthesis site of 1,25- dihydroxyvitamin D3 (biologicallyactiveform) VDR: vitamin D receptor Adorini L et al Ann N.Y. Acad Sci 2010

37. Calcitriol • 1. Inhibits the espressionof COX2 • (synthesisof PG) • 2. Inductionof the expressionof 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PG) • 3. Decreasing the expression of prostaglandin E and prostaglandin F PG receptors Krishnam AV et al J Bon Min Res 2007

38. Elocalcitol (orally 5 days/wk at 100 g/kg for 2 wk) inhibits the intraprostatic cell infiltrate and cell proliferation and increased apoptosis Dex: dexamethasone Penna G et al J Immunol 2006

39. Peixoto CA et al Journal of Inflammation 2015

40. Tadalafil and vardenafil inhibit TNFa-induced secretion of IL-8 and IP-10 by hBPHcells Vignozzi L et al Prostate 2013

41. Patients with MetS had significantly higher CD45 score, as compared to the rest of the sample In the MetS cohort there was a statistically significant lower CD45 score in the vardenafil arm as compared to placebo vardenafil did not affect CD45 score in patients without MetS Vignozzi L et al Prostate 2013

42. PDE5i Hamilton TK et al W J Urol 2013

43. Inflammation within index tumors of 236 men undergoing RP Preoperative statin use (statin users or nonusers) Statin use ≥1 DE before surgery was significantly associated with lower risk for any tumor inflammation DE: dose equivalent 1= 20 mg Bañez L et al Cancer Epidemiol Biomarkers 2010

44. Other (Vitamin D, statin, PDE5i) • Dati sperimentali in vitro e sul modello murino promettenti • Limitate evidenze in studi clinici, randomizzati, placebo-controllati • Possibili sviluppi futuri?

45. Conclusioni • Definire il ruolo della flogosi nel cancro della prostata • Comprendere i complessi meccanismi di correlazione • Individuare delle opzioni terapeutiche con riscontri istologici e clinici di comprovata efficacia • Condividere le competenze (approccio multidisciplinare) Evidence base medicine

46. Grazie per l’attenzione