Prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PC) are the three diseases of the prostate that threaten the physical and mental health of men over 50.

Prostatitis

Traditionally, the term ÔÇ£prostatitisÔÇØ includes both bacterial forms (acute and chronic) and non-bacterial chronic prostatitis and chronic pelvic pain syndrome. There is also an asymptomatic inflam- matory form that can only be detected histologically 1 Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on urological infections. Euro- pean Association of Urology 2011; p. 65-72. .

From an aetiological viewpoint, the most frequent pathogens isola- ted in bacterial prostatitis are: Escherichia coli, Klebsiella spp, Proteus mirabilis, Enterococcus faecalis and Pseudomonas aeruginosa. Other microorganisms (Chlamydia trachomatis, Ureaplasma urealyti- cum, Mycoplasma hominis) have been reported whose significance is uncertain 2 Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on urological infections. Euro- pean Association of Urology 2011; p. 65-72. . Acute prostatitis is characterised by pain predominantly localised in the genital area, fever, urinary frequency and urgency, dysuria and sometimes acute urinary retention. In chronic prostatitis, the symptoms persist with varying intensity for at least three months. Chronic pelvic pain syndrome is defined mainly by exclusion criteria and urological pain is the main component 3 Magri V, Perletti G, Bartoletti R, et al. Critical issues in chronic prostatitis. Arch Ital Urol An- drol. 2010; 82:75-82. . It should be noted that chronic prostatitis is often accompanied by sexual dysfunction 4 Trinchieri A, Magri V, Cariani L, et al. Prevalence of sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome. Arch Ital Urol Androl. 2007; 79:67-70. 5
Lee SW, Liong ML, Yuen KH, et al.Adverse impact of sexual dysfunction in chronic prostatitis/chronic pelvic pain syndrome. Urology. 2008; 71:79-84.
. Antibiotics are life-saving drugs in acute prostatitis, they are recom- mended in chronic bacterial forms and are used on an empirical basis in forms with only an inflammatory component 6 \Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on urological infections. Euro- pean Association of Urology 2011; p. 65-72. 7
Magri V, Perletti G, Bartoletti R, et al. Critical issues in chronic prostatitis. Arch Ital Urol An- drol. 2010; 82:75-82.
. Due to their pharmacokinetic properties, fluoroquinolones are consi- dered the antibiotics of choice for these conditions and treatment duration varies between two and six weeks
8 \Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on urological infections. Euro- pean Association of Urology 2011; p. 65-72. 9
Magri V, Perletti G, Bartoletti R, et al. Critical issues in chronic prostatitis. Arch Ital Urol An- drol. 2010; 82:75-82.
In addition to their impact on quality of life, forms of chronic prosta- titis also play an important part in the pathogenesis of PC 10 De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7:256-69 . The connection between chronic inflammation and cancer is not a recent idea because it was reported for the first time by Virchow in 1863 11 Balkwill F, Mantovani A.Inflammation and cancer: back to Virchow? Lancet. 2001; 357:539-45 . Regarding the relationship between chronic prostatitis and PC, re- cently Elkahwaji, et al. showed, in an animal model, that chronic bac- terial inflammation of the prostate induces atypical glandular foci in this organ (prostatic intraepithelial neoplasia) that are the results of oxidative stress due to inflammation 12 Elkahwaji JE, Hauke RJ, Brawner CM. Chronic bacterial inflammation induces prostatic in- traepithelial neoplasia in mouse prostate. Br J Cancer. 2009; 101:1740-8 . The inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) that destroy the bacteria and also in the long run cause oxidative damage to cellular DNA leading to changes in the genome (point mutations, deletions, rearrange- ments), which play a crucial role in the process of carcinogenesis 13 Oberley TD. Oxidative damage and cancer. Am J Pathol. 2002; 160:403-8. . In addition, bacterial LPS (lipopolysaccharide) activates TLR4 (Toll- Like Receptor 4) and the NF╬║B (Nuclear Factor-kappa B) pathway, which in turn induce IL-6 (interleukine 6), COX-2 (cyclo-oxygenase 2) and LOXs (lipoxygenase) 14 Kundu SD, Lee C, Billips BK, et al. The toll-like receptor pathway: a novel mechanism of in- fection-induced carcinogenesis of prostate epithelial cells. Prostate. 2008; 68:223-9. . IL-6 is an important mitogen for normal prostatic cells and for androgen-independent cells and can contribute to the androgen- independence of PC due to its ability to activate the androgen receptor 15 Corcoran NM, Costello AJ.Interleukin-6: minor player or starring role in the development of hor- mone-refractory prostate cancer? BJU Int 2003; 91:545-53. . The activity of COX-2 and LOXs generates 4-HNE (4-hydroxynonenal) and MDA (malondialdehyde), bioproducts that further stimulate the inflammatory response. In this context, it has been demonstrated that in cell cultures lyco – pene down-regulates many substances involved in inflammation such as cytokines, enzymes and transcription factors 16 De Stefano D, Maiuri MC, Simeon V, et al. Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-gamma. Eur J Pharmacol. 2007; 566:192ÔÇô199 17 Huang CS, Fan YE, Lin CY, Hu ML. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. J Nutr Biochem. 2007; 18:449-56. 18 Herzog A, Siler U, Spitzer V, et al. Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J. 2005; 19:272-4. 19 Siler U, Barella L, Spitzer V, et al. Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. FASEB J. 2004; 18:1019-21. 20 Kim GY, Kim JH, Ahn SC, et al. Lycopene suppresses the lipopolysaccharide-induced pheno- typic and functional maturation of murine dendritic cells through inhibition of mitogen-activat- ed protein kinases and nuclear factor-kappa B. Immunology. 2004; 113:203-11. 21 Bessler H, Salman H, Bergman M, et al. In vitro effect of lycopene on cytokine production by human peripheral blood mononuclear cells. Immunol Invest. 2008; 37:183-90. . In chronic bacterial prostatitis, the action of lycopene in vivo has been studied in rats where it has been shown that this carotenoid acts synergistically with cyprofloxacin in reducing bacterial growth and improving inflammatory symptoms 22 Han CH, Yang CH, Sohn DW, et al. Synergistic effect between lycopene and ciprofloxacin on a chronic bacterial prostatitis rat model. Int J Antimicrob Agents. 2008; 31 Suppl 1:S102-7. . The synergistic action of lycopene with other active substances in improving the clinical symptoms of prostatitis has also been highlighted very recently in humans: in patients with chronic prostatitis/chronic pelvic pain, lycopene in combination with Serenoa repens and selenium was found to enhance the positive effects on prostate symptoms, urine flow and PSA 23 Morgia G, Mucciardi G, Gal├¼ A, et al. Treatment of chronic prostatitis/chronic pelvic pain syndrome category IIIA with Serenoa repens plus selenium and lycopene (Profluss) versus S. repens alone: an Italian randomized multicenter-controlled study. Urol Int. 2010; 84:400-6. .

Benign prostatic hyperplasia

BPH is characterised by an enlarged prostate due to hyper- plasia of cells that constitute the stromal and glandular component of this organ 24 Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hy- perplasia with age. J Urol. 1984; 132:474-9. . It is a very common condition in men over the age of 50, reaching a rate of 80% after the age of 80 25 Blom JH, Schr├Âder FH. Epidemiology and natural course of benign prostatic hyperplasia. Urologe A. 1992; 31:129-34. . BPH is a progressive disease that causes annoying and worrisome lo- wer urinary tract symptoms (LUTS) such as urinary frequency and urgency, nocturia, decreased and intermittent urinary stream and sensation of incomplete bladder emptying. The relationship between BPH and LUTS is complex because not all men with BPH have significant LUTS and not all men with LUTS have BPH 26 Emberton M, Cornel EB, Bassi PF, et al. Benign prostatic hyperplasia as a progressive dis- ease: a guide to the risk factors and options for medical management. Int J Clin Pract. 2008; 62:1076-86. . Progression of BPH is indicated by the worsening of urinary symptoms, deterioration in urinary flow, an increase in prostate volume, the onset of acute urinary retention (AUR) and the need for surgery due to the AUR or because of the symptoms 27 Emberton M, Andriole GL, de la Rosette J, et al. Benign prostatic hyperplasia: a progres- sive disease of aging men. Urology. 2003; 61:267-73. . In the placebo arm of the MTOPS (Medical Therapy Of Prostatic Symptoms) study, symptoms were reported to worsen over a four-year period in 17.4% of cases 28 McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finas- teride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003; 349:2387-98. and the VeteranÔÇÖs Affairs Study demonstrated that 36% of men with BPH in whom a strategy of ÔÇ£watchful waitingÔÇØ was adopted had to undergo invasive treatment within five years 29 Flanigan RC, Reda DJ, Wasson JH, et al. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans Affairs cooperative study. J Urol. 1998; 160:12-6; discussion 16-7. . Many factors are involved in the pathogenesis of BPH: androgens certainly play a permissive role, but oestrogens, epithelial-stromal interactions, the prostatic vascular system, altered gene expression and inflammation are also important 30
Tang J, Yang J.Etiopathogenesis of benign prostatic hyperplasia. Indian J Urol. 2009; 25:312-7.
. The latter is a very frequent histological finding in BPH [78% of cases in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study 31
Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflamma- tion and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008; 54:1379-84.
] and a very recent and comprehensive review highlighted the possibility that inflammation may promote the progression of BPH and act as the link between this condition and PC 32 De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between be- nign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol. 2011; 60:106-17 . On the other hand, as previously illustrated for prostatitis, chronic inflammation produces oxidative stress, which if not removed by the natural defence systems (e.g. superoxide dismutase, glutathione peroxidase and catalase) gives rise to DNA damage that underpins the development of proliferative diseases of the prostrate 33 Hamid AR, Umbas R, Mochtar CA. Recent role of inflammation in prostate diseases: chemo- prevention development opportunity. Acta Med Indones. 2011; 43:59-65 . These findings, in addition to the observation that current oral treatments for BPH do not protect against the serious adverse events of this condition (renal failure, AUR, bladder stones, urinary infections) 34
Stroup SP, Palazzi-Churas K, Kopp RP, Parsons JK. Trends in adverse events of benign pro- static hyperplasia (BPH) in the USA, 1998 to 2008. BJU Int. 2012; 109:84-7.
, seem to indicate a need to add new substances capable of anti-inflammatory and antioxidant actions to more tried and
Lycopene application in human disease tested conservative treatments. Lycopene is known to build up significantly in the prostate 35 Clinton SK, Emenhiser C, Schwartz SJ, et al. Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev. 1996; 5:823-33. where it inhibits the synthesis of various molecules involved in the inflammatory process (see prostatitis). Alongside this anti-inflammatory activity, lycopene has also been shown to down-regulate the androgenic signal (androgens are the main mitogens of prostatic cells) 36 Wertz K. Lycopene effects contributing to prostate health. Nutr Cancer. 2009; 61:775-83. , although not a ligand of the androgen receptor 37 Denmeade SR, Sokoll LJ, Dalrymple S, et al. Dissociation between androgen responsive- ness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. Prostate. 2003; 54:249-57. . In the prevention of symptomatic BPH, analysis of data from the placebo group in the PCPT (Prostate Cancer Prevention Trial), made up of 4470 subjects who were devoid of this condition at baseline suggests that high daily doses of lycopene reduce the risk of developing this condition 38 Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008; 167:925-34. . When tested in vivo in patients with BPH in the form of a tomato sauce or concentrate, lycopene was shown to increase the apoptosis of prostate cells and reduced plasma levels of PSA 39 Kim HS, Bowen P, Chen L, et al. Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer. 2003; 47:40-7 40
Edinger MS, Koff WJ. Effect of the consumption of tomato paste on plasma prostate-specific antigen levels in patients with benign prostate hyperplasia. Braz J Med Biol Res. 2006; 39:1115-9
, whose encoding gene is a target for androgens 41 Denmeade SR, Sokoll LJ, Dalrymple S, et al. Dissociation between androgen responsive- ness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. Prostate. 2003; 54:249-57. . The in vivo effect on PSA was confirmed by a double blind clinical trial versus placebo, which also showed that in patients with BPH, lycopene has a positive influence on some disease progression indicators such as urinary symptoms and prostatic volume over six months of supplementation without the aid of ad hoc drugs 42 Schwarz S, Oberm├╝ller-Jevic UC, Hellmis E, et al. Lycopene inhibits disease progression in patients with benign prostate hyperplasia. J Nutr. 2008; 138:49-53. (Figure 1).

Prostate cancer

More recent data from the American Cancer Society indicate that PC is the most common human cancer in the US and is the second leading cause of cancer mortality in males 43 American Cancer Society. Cancer Facts and Figures 2012 . The incidence of this cancer has increased dramatically in recent decades, primarily because of the instruments for its early identifica- tion, such as PSA and transrectal ultrasound. In the early stages, PC is usually asymptomatic but disease progression is accompanied by LUTS, haematuria and difficulty and pain on urination. In the advanced stages, the symptoms are caused by metastases, most frequently affecting the bones.

Although androgens stimulate the growth and proliferation of normal and neoplastic prostatic cells, high circulating levels of these hormones do not represent a risk factor for the development of PC 44 Severi G, Morris HA, MacInnis RJ, et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006; 15:86-91. 45 Muller RL, Gerber L, Moreira DM, et al. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol. 2012; 62:757-64. . The only well-established risk factors for the onset of PC are age, ethnicity/race, family history and certain environmental factors, such as diet 46 Muller RL, Gerber L, Moreira DM, et al. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol. 2012; 62:757-64. . Regarding diet, it has been shown that the calorific excess and foods of animal origin, which are typical of the Western diet, such as dairy products and meat, are associated with PC, while consumption of vegetables and fruit protect against PC 47 Heidenreich A, Bolla M, Joniau S, et al. Guidelines on Pro-state Cancer. European Associa- tion of Urology 2011; p. 10-11. . The term chemoprevention describes the use of specific synthetic or natural (dietary) substances to prevent, delay or slow down the pro- cess of carcinogenesis. As far as PC is concerned, it has been found that two inhibitors (fina- steride and dutasteride) of 5 alpha-reductase (the enzyme that cata- lyses the synthesis of 5 alfa-dihydrotestosterone) reduced the risk of developing cancer by 25%, but in December 2010 the Oncologic Drugs Advisory Committee of the Food and Drug Administration spoke out against approving this therapeutic use because both drugs did not display a favourable risk/benefit profile when used in the chemo- prevention of PC in healthy men 48 Theoret MR, Ning Y-M, Zhang JJ, et al. The risks and benefits of 5╬▒-reductase inhibitors for prostate-cancer prevention N Engl J Med 2011; 365:97-99. . The American Cancer Society, on the other hand, suggests that a diet rich in lycopene can reduce the risk of PC 49 American Cancer Society. Cancer Facts and Figures 2010 . From a molecular biology viewpoint, this is possible because the lyco pene, as well as exerting an anti-inflammatory action and down- regulating the activation of androgen and its signal (see prostatitis and BPH), has also been shown to inhibit IGF-1 (Insulin-like Growth Factor-1) both in the rat 50 Siler U, Herzog A, Spitzer V, et al. Lycopene effects on rat normal prostate and prostate tumor tissue. J Nutr. 2005; 135:2050S-2S. and in humans 51 Riso P, Brusamolino A, Martinetti A, Porrini M. Effect of a tomato drink intervention on insulin-like growth factor (IGF)-1 serum levels in healthy subjects. Nutr Cancer. 2006; 55:157-62. . It should be noted that high serum levels of this growth factor are associated with an increased risk of PC 52 Pollak M. Insulin-like growth factors and prostate cancer. Epidemiol Rev. 2001; 23:59-66. , that its over-expression in the prostatic epithelium gives rise to epithelial hyperplasia 53
Kaplan-Lefko PJ, Sutherland BW, Evangelou AI, et al. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene. 2008; 27:2868-76.
and prostatic intraepithelial neoplasia 54 DiGiovanni J, Kiguchi K, Frijhoff A, et al. Deregulated expression of insulin-like growth fac- tor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A. 2000; 97:3455-60. and that the signals it mediates are important for the progression of PC to a state of androgen- independence 55
Wertz K. Lycopene effects contributing to prostate health. Nutr Cancer. 2009; 61:775-83.
5.

Molecular effects promoting the chemopreventive action performed by lycopene against cancers also include its ability to inhibit DNA synthesis 54 (Figure 2), induce phase II enzymes 56 Breinholt V, Lauridsen ST, Daneshvar B, Jakobsen J. Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett. 2000; 154:201-210. , increase the expression of Cx43 (gap junction protein reduced in tumours) 57 Fornelli F, Leone A, Verdesca I, et al. The influence of lycopene on the proliferation of hu man breast cell line (MCF-7). Toxicol In Vitro. 2007; 21:217-23 58 Chalabi N, Delort L, Satih S, et al. Immunohistochemical expression of RARalpha, RARbeta, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR. J Histochem Cytochem. 2007; 55:877-83. and stimulate apoptosis 59 Ivanov NI, Cowell SP, Brown P, et al. Lycopene differentially induces quiescence and apop- tosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr. 2007; 26:252-63. . The results of some epidemiological studies conducted to evaluate the consumption of tomatoes and their derivatives or whether supplementation with lycopene can effectively reduce the risk of PC have been positive 60 Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002; 94:391-8. 61 Wu K, Erdman JW Jr, Schwartz SJ, et al. Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2004; 13:260-9. 62 Etminan M, Takkouche B, Caama├▒o-Isorna F. The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev. 2004; 13:340-5. 63 Shahar S, Shafurah S, Hasan Shaari NS, et al. Roles of diet, lifetime physical activity and oxidative DNA damage in the occurrence of prostate cancer among men in Klang Valley, Malaysia. Asian Pac J Cancer Prev. 2011; 12:605-11. . In particular, the Health Professional Follow-up Study showed that consuming 2-4 servings/week of tomato sauce is associated with a 35% reduction in the risk of PC 64
Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate can- cer. Exp Biol Med (Maywood). 2002; 227:852-9.
. Since the serum concentration of lycopene is an expression of the consumption of tomatoes and their derivatives 65 Ganji V, Kafai MR. Third National Health and Nutrition Examination Survey, 1998-1994. Population determinants of serum lycopene concentrations in the United States: data from the Third National Health and Nutrition Examination Survey, 1988-1994. J Nutr. 2005; 135:567-72. , some authors have investigated the relationship between this parameter and the risk of PC. A meta-analysis of studies conducted by a panel of experts from the

Figure 2 In prostate cancer cells, lycopene inhibits DNA synthesis in a dose-dependent manner in vitro. Modified from 66
Zhang X, Wang Q, Neil B, Chen X. Effect of lycopene on androgen receptor and prostate- specific antigen velocity. Chin Med J (Engl). 2010; 123:2231-6.

World Cancer Research Fund and the American Institute for Cancer Research revealed that each 10 mg/L increment in serum lycopene concentration is associated with a 4% reduction in the risk of PC 67
World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR, 2007; p.104
. An analysis of data from the PCPT did not however confirm this report 68 Kristal AR, Till C, Platz EA, et al. Serum lycopene concentration and prostate cancer risk: results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2011; 20:638ÔÇô646. , but these comments were immediately criticised and inter – esting alternative interpretations were offered 69
Giovannucci E. Commentary: Serum lycopene and prostate cancer progression: a re-consid- eration of findings from the prostate cancer prevention trial. Cancer Causes Control. 2011; 22:1055-9.
70
Wei MY, Giovannucci EL. Lycopene, tomato products, and prostate cancer incidence: a re- view and reassessment in the PSA screening era. J Oncol. 2012; 2012:271063.
. In the course of high-grade prostatic intraepithelial neoplasia (HGPIN, a precursor of CaP) the use of lycopene may delay or prevent the development of occult PC 71
Mohanty NK, Saxena S, Singh UP, et al. Lycopene as a chemopreventive agent in the treat- ment of high-grade prostate intraepithelial neoplasia. Urol Oncol. 2005; 23:383-5.
, while when this condition is already present and diagnosed, lycopene reduces serum levels of PSA and tumour volume 72 Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supple- mentation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev. 2001; 10:861-8. 73 Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Can- cer Inst. 2001; 93:1872-9. 74 Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. 2003; 92:375-8; discussion 378. Erratum in: BJU Int. 2004; 93:655. . It has been demonstrated that when PC becomes resistant to androgen-deprivation therapy, the use of docetaxel increases survival, albeit only slightly 75 Dagher R, Li N, Abraham S, et al. Approval summary: Docetaxel in combination with pred- nisone for the treatment of androgen-independent hormone-refractory prostate cancer. Clin Cancer Res. 2004; 10:8147-51. ; experimental studies have shown that in PC cases that over-express the receptor for IGF-1, lyco- pene potently enhances the antitumour activity of docetaxel in vitro and in vivo, opening new therapeutic perspectives for patients with advanced PC 76 Tang Y, Parmakhtiar B, Simoneau AR, et al. Lycopene enhances docetaxel’s effect in cas- tration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia. 2011; 13:108-19. (Figure 3).

A very recent review of randomised clinical trials on the use of lycopene in the prevention and treatment of BPH and PC concluded that the small number of trials and their variable quality means that definitive conclusions cannot be drawn about the effective role of this natural antioxidantm 77 Ilic D, Misso M. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: a systematic review. Maturitas. 2012; 72:269-76. 75.

References

1. http://www.ncbi.nlm.nih.gov/pubmed consultato in data 25/10/2012.

2. Miller ES, Mackinney G, Zscheile FP. Absorption spectra of alpha and beta carotenes and ly- copene. Plant Physiol. 1935; 10:375-81.

3. Ismail MF, Mohamed HM. Modulatory effect of lycopene on deltamethrin-induced testicular injury in rats. Cell Biochem Biophys. 2012 Oct 18. [Epub ahead of print].

4. Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on urological infections. Euro- pean Association of Urology 2011; p. 65-72.

5. Magri V, Perletti G, Bartoletti R, et al. Critical issues in chronic prostatitis. Arch Ital Urol An- drol. 2010; 82:75-82.

6. Trinchieri A, Magri V, Cariani L, et al. Prevalence of sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome. Arch Ital Urol Androl. 2007; 79:67-70.

7. Lee SW, Liong ML, Yuen KH, et al.Adverse impact of sexual dysfunction in chronic prostatitis/chronic pelvic pain syndrome. Urology. 2008; 71:79-84.

8. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7:256-69

9. Balkwill F, Mantovani A.Inflammation and cancer: back to Virchow? Lancet. 2001; 357:539-45

10. Elkahwaji JE, Hauke RJ, Brawner CM. Chronic bacterial inflammation induces prostatic in- traepithelial neoplasia in mouse prostate. Br J Cancer. 2009; 101:1740-8

11. Oberley TD. Oxidative damage and cancer. Am J Pathol. 2002; 160:403-8.

12. Kundu SD, Lee C, Billips BK, et al. The toll-like receptor pathway: a novel mechanism of in- fection-induced carcinogenesis of prostate epithelial cells. Prostate. 2008; 68:223-9.

13. Corcoran NM, Costello AJ.Interleukin-6: minor player or starring role in the development of hor- mone-refractory prostate cancer? BJU Int 2003; 91:545-53.

15. Wertz K. Lycopene effects contributing to prostate health. Nutr Cancer. 2009; 61:775-83.

16. De Stefano D, Maiuri MC, Simeon V, et al. Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-gamma. Eur J Pharmacol. 2007; 566:192ÔÇô199

17. Huang CS, Fan YE, Lin CY, Hu ML. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. J Nutr Biochem. 2007; 18:449-56.

18. Herzog A, Siler U, Spitzer V, et al. Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J. 2005; 19:272-4.

19. Siler U, Barella L, Spitzer V, et al. Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. FASEB J. 2004; 18:1019-21.

20. Kim GY, Kim JH, Ahn SC, et al. Lycopene suppresses the lipopolysaccharide-induced pheno- typic and functional maturation of murine dendritic cells through inhibition of mitogen-activat- ed protein kinases and nuclear factor-kappa B. Immunology. 2004; 113:203-11.

21. Bessler H, Salman H, Bergman M, et al. In vitro effect of lycopene on cytokine production by human peripheral blood mononuclear cells. Immunol Invest. 2008; 37:183-90.

22. Han CH, Yang CH, Sohn DW, et al. Synergistic effect between lycopene and ciprofloxacin on a chronic bacterial prostatitis rat model. Int J Antimicrob Agents. 2008; 31 Suppl 1:S102-7.

23. Morgia G, Mucciardi G, Galì A, et al. Treatment of chronic prostatitis/chronic pelvic pain syndrome category IIIA with Serenoa repens plus selenium and lycopene (Profluss) versus S. repens alone: an Italian randomized multicenter-controlled study. Urol Int. 2010; 84:400-6.

24. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hy- perplasia with age. J Urol. 1984; 132:474-9.

25. Blom JH, Schr├Âder FH. Epidemiology and natural course of benign prostatic hyperplasia. Urologe A. 1992; 31:129-34.

26. Emberton M, Cornel EB, Bassi PF, et al. Benign prostatic hyperplasia as a progressive dis- ease: a guide to the risk factors and options for medical management. Int J Clin Pract. 2008; 62:1076-86.

27. Emberton M, Andriole GL, de la Rosette J, et al. Benign prostatic hyperplasia: a progres- sive disease of aging men. Urology. 2003; 61:267-73.

28. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finas- teride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003; 349:2387-98.

29. Flanigan RC, Reda DJ, Wasson JH, et al. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans Affairs cooperative study. J Urol. 1998; 160:12-6; discussion 16-7.

30. Tang J, Yang J.Etiopathogenesis of benign prostatic hyperplasia. Indian J Urol. 2009; 25:312-7.

31. Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflamma- tion and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008; 54:1379-84.

32. De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between be- nign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol. 2011; 60:106-17

33. Hamid AR, Umbas R, Mochtar CA. Recent role of inflammation in prostate diseases: chemo- prevention development opportunity. Acta Med Indones. 2011; 43:59-65

34. Stroup SP, Palazzi-Churas K, Kopp RP, Parsons JK. Trends in adverse events of benign pro- static hyperplasia (BPH) in the USA, 1998 to 2008. BJU Int. 2012; 109:84-7.

35. Clinton SK, Emenhiser C, Schwartz SJ, et al. Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev. 1996; 5:823-33.

36. Liu A, Pajkovic N, Pang Y, et al. Absorption and subcellular localization of lycopene in human prostate cancer cells. Mol Cancer Ther. 2006; 5:2879-85.

37. Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008; 167:925-34.

38. Kim HS, Bowen P, Chen L, et al. Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer. 2003; 47:40-7

39. Edinger MS, Koff WJ. Effect of the consumption of tomato paste on plasma prostate-specific antigen levels in patients with benign prostate hyperplasia. Braz J Med Biol Res. 2006; 39:1115-9

40. Denmeade SR, Sokoll LJ, Dalrymple S, et al. Dissociation between androgen responsive- ness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. Prostate. 2003; 54:249-57.

41. Schwarz S, Oberm├╝ller-Jevic UC, Hellmis E, et al. Lycopene inhibits disease progression in patients with benign prostate hyperplasia. J Nutr. 2008; 138:49-53.

42. American Cancer Society. Cancer Facts and Figures 2012

43. Severi G, Morris HA, MacInnis RJ, et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006; 15:86-91.

44. Muller RL, Gerber L, Moreira DM, et al. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol. 2012; 62:757-64.

45. Heidenreich A, Bolla M, Joniau S, et al. Guidelines on Pro-state Cancer. European Associa- tion of Urology 2011; p. 10-11.

46. Stacewicz-Sapuntzakis M, Borthakur G, Burns JL, Bowen PE. Correlations of dietary pat- terns with prostate health. Mol Nutr Food Res. 2008; 52:114-30.

47. Theoret MR, Ning Y-M, Zhang JJ, et al. The risks and benefits of 5╬▒-reductase inhibitors for prostate-cancer prevention N Engl J Med 2011; 365:97-99.

48. American Cancer Society. Cancer Facts and Figures 2010

49. Siler U, Herzog A, Spitzer V, et al. Lycopene effects on rat normal prostate and prostate tu- mor tissue. J Nutr. 2005; 135:2050S-2S.

50. Riso P, Brusamolino A, Martinetti A, Porrini M. Effect of a tomato drink intervention on insulin-like growth factor (IGF)-1 serum levels in healthy subjects. Nutr Cancer. 2006; 55:157-62.

51. Pollak M. Insulin-like growth factors and prostate cancer. Epidemiol Rev. 2001; 23:59-66.

52. Kaplan-Lefko PJ, Sutherland BW, Evangelou AI, et al. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene. 2008; 27:2868-76.

53. DiGiovanni J, Kiguchi K, Frijhoff A, et al. Deregulated expression of insulin-like growth fac- tor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A. 2000; 97:3455-60.

54. Zhang X, Wang Q, Neil B, Chen X. Effect of lycopene on androgen receptor and prostate- specific antigen velocity. Chin Med J (Engl). 2010; 123:2231-6.

55. Breinholt V, Lauridsen ST, Daneshvar B, Jakobsen J. Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett. 2000; 154:201-210.

56. Fornelli F, Leone A, Verdesca I, et al. The influence of lycopene on the proliferation of hu man breast cell line (MCF-7). Toxicol In Vitro. 2007; 21:217-23

57. Chalabi N, Delort L, Satih S, et al. Immunohistochemical expression of RARalpha, RARbeta, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR. J Histochem Cytochem. 2007; 55:877-83.

58. Ivanov NI, Cowell SP, Brown P, et al. Lycopene differentially induces quiescence and apop- tosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr. 2007; 26:252-63.

59. Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002; 94:391-8.

60. Wu K, Erdman JW Jr, Schwartz SJ, et al. Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2004; 13:260-9.

61. Etminan M, Takkouche B, Caama├▒o-Isorna F. The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev. 2004; 13:340-5.

62. Shahar S, Shafurah S, Hasan Shaari NS, et al. Roles of diet, lifetime physical activity and oxidative DNA damage in the occurrence of prostate cancer among men in Klang Valley, Malaysia. Asian Pac J Cancer Prev. 2011; 12:605-11.

63. Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate can- cer. Exp Biol Med (Maywood). 2002; 227:852-9.

64. Ganji V, Kafai MR. Third National Health and Nutrition Examination Survey, 1998-1994. Population determinants of serum lycopene concentrations in the United States: data from the Third National Health and Nutrition Examination Survey, 1988-1994. J Nutr. 2005; 135:567-72.

65. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR, 2007; p.104

66. Kristal AR, Till C, Platz EA, et al. Serum lycopene concentration and prostate cancer risk: results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2011; 20:638ÔÇô646.

67. Giovannucci E. Commentary: Serum lycopene and prostate cancer progression: a re-consid- eration of findings from the prostate cancer prevention trial. Cancer Causes Control. 2011; 22:1055-9.

68. Wei MY, Giovannucci EL. Lycopene, tomato products, and prostate cancer incidence: a re- view and reassessment in the PSA screening era. J Oncol. 2012; 2012:271063.

69. Mohanty NK, Saxena S, Singh UP, et al. Lycopene as a chemopreventive agent in the treat- ment of high-grade prostate intraepithelial neoplasia. Urol Oncol. 2005; 23:383-5.

70. Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supple- mentation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev. 2001; 10:861-8.

71. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Can- cer Inst. 2001; 93:1872-9.

72. Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. 2003; 92:375-8; discussion 378. Erratum in: BJU Int. 2004; 93:655.

73. Dagher R, Li N, Abraham S, et al. Approval summary: Docetaxel in combination with pred- nisone for the treatment of androgen-independent hormone-refractory prostate cancer. Clin Cancer Res. 2004; 10:8147-51.

74. Tang Y, Parmakhtiar B, Simoneau AR, et al. Lycopene enhances docetaxel’s effect in cas- tration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia. 2011; 13:108-19.

75. Ilic D, Misso M. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: a systematic review. Maturitas. 2012; 72:269-76.


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35. Clinton SK, Emenhiser C, Schwartz SJ, et al. Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev. 1996; 5:823-33.
36. Wertz K. Lycopene effects contributing to prostate health. Nutr Cancer. 2009; 61:775-83.
37, 41. Denmeade SR, Sokoll LJ, Dalrymple S, et al. Dissociation between androgen responsive- ness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. Prostate. 2003; 54:249-57.
38. Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008; 167:925-34.
39. Kim HS, Bowen P, Chen L, et al. Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer. 2003; 47:40-7
40.
Edinger MS, Koff WJ. Effect of the consumption of tomato paste on plasma prostate-specific antigen levels in patients with benign prostate hyperplasia. Braz J Med Biol Res. 2006; 39:1115-9
42. Schwarz S, Oberm├╝ller-Jevic UC, Hellmis E, et al. Lycopene inhibits disease progression in patients with benign prostate hyperplasia. J Nutr. 2008; 138:49-53.
43. American Cancer Society. Cancer Facts and Figures 2012
44. Severi G, Morris HA, MacInnis RJ, et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006; 15:86-91.
45, 46. Muller RL, Gerber L, Moreira DM, et al. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol. 2012; 62:757-64.
47. Heidenreich A, Bolla M, Joniau S, et al. Guidelines on Pro-state Cancer. European Associa- tion of Urology 2011; p. 10-11.
48. Theoret MR, Ning Y-M, Zhang JJ, et al. The risks and benefits of 5╬▒-reductase inhibitors for prostate-cancer prevention N Engl J Med 2011; 365:97-99.
49. American Cancer Society. Cancer Facts and Figures 2010
50. Siler U, Herzog A, Spitzer V, et al. Lycopene effects on rat normal prostate and prostate tumor tissue. J Nutr. 2005; 135:2050S-2S.
51. Riso P, Brusamolino A, Martinetti A, Porrini M. Effect of a tomato drink intervention on insulin-like growth factor (IGF)-1 serum levels in healthy subjects. Nutr Cancer. 2006; 55:157-62.
52. Pollak M. Insulin-like growth factors and prostate cancer. Epidemiol Rev. 2001; 23:59-66.
53.
Kaplan-Lefko PJ, Sutherland BW, Evangelou AI, et al. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene. 2008; 27:2868-76.
54. DiGiovanni J, Kiguchi K, Frijhoff A, et al. Deregulated expression of insulin-like growth fac- tor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A. 2000; 97:3455-60.
55.
Wertz K. Lycopene effects contributing to prostate health. Nutr Cancer. 2009; 61:775-83.
56. Breinholt V, Lauridsen ST, Daneshvar B, Jakobsen J. Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett. 2000; 154:201-210.
57. Fornelli F, Leone A, Verdesca I, et al. The influence of lycopene on the proliferation of hu man breast cell line (MCF-7). Toxicol In Vitro. 2007; 21:217-23
58. Chalabi N, Delort L, Satih S, et al. Immunohistochemical expression of RARalpha, RARbeta, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR. J Histochem Cytochem. 2007; 55:877-83.
59. Ivanov NI, Cowell SP, Brown P, et al. Lycopene differentially induces quiescence and apop- tosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr. 2007; 26:252-63.
60. Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002; 94:391-8.
61. Wu K, Erdman JW Jr, Schwartz SJ, et al. Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2004; 13:260-9.
62. Etminan M, Takkouche B, Caama├▒o-Isorna F. The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev. 2004; 13:340-5.
63. Shahar S, Shafurah S, Hasan Shaari NS, et al. Roles of diet, lifetime physical activity and oxidative DNA damage in the occurrence of prostate cancer among men in Klang Valley, Malaysia. Asian Pac J Cancer Prev. 2011; 12:605-11.
64.
Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate can- cer. Exp Biol Med (Maywood). 2002; 227:852-9.
65. Ganji V, Kafai MR. Third National Health and Nutrition Examination Survey, 1998-1994. Population determinants of serum lycopene concentrations in the United States: data from the Third National Health and Nutrition Examination Survey, 1988-1994. J Nutr. 2005; 135:567-72.
66.
Zhang X, Wang Q, Neil B, Chen X. Effect of lycopene on androgen receptor and prostate- specific antigen velocity. Chin Med J (Engl). 2010; 123:2231-6.
67.
World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR, 2007; p.104
68. Kristal AR, Till C, Platz EA, et al. Serum lycopene concentration and prostate cancer risk: results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2011; 20:638ÔÇô646.
69.
Giovannucci E. Commentary: Serum lycopene and prostate cancer progression: a re-consid- eration of findings from the prostate cancer prevention trial. Cancer Causes Control. 2011; 22:1055-9.
70.
Wei MY, Giovannucci EL. Lycopene, tomato products, and prostate cancer incidence: a re- view and reassessment in the PSA screening era. J Oncol. 2012; 2012:271063.
71.
Mohanty NK, Saxena S, Singh UP, et al. Lycopene as a chemopreventive agent in the treat- ment of high-grade prostate intraepithelial neoplasia. Urol Oncol. 2005; 23:383-5.
72. Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supple- mentation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev. 2001; 10:861-8.
73. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Can- cer Inst. 2001; 93:1872-9.
74. Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. 2003; 92:375-8; discussion 378. Erratum in: BJU Int. 2004; 93:655.
75. Dagher R, Li N, Abraham S, et al. Approval summary: Docetaxel in combination with pred- nisone for the treatment of androgen-independent hormone-refractory prostate cancer. Clin Cancer Res. 2004; 10:8147-51.
76. Tang Y, Parmakhtiar B, Simoneau AR, et al. Lycopene enhances docetaxel’s effect in cas- tration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia. 2011; 13:108-19.
77. Ilic D, Misso M. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: a systematic review. Maturitas. 2012; 72:269-76.