**6. Phytoestrogens in human CRC**

Several studies have reported a reduction of the CRC risk associated with the consumption of soy foods (the main source of isoflavones) and non-fermented soy foods (e.g. tofu) (47- 52). The main limitations of these studies are that they all assessed only specific soy foods intake rather than total phytoestrogen intake: none of the studies was designed to evaluate phytoestrogen intake.

Another study investigated the association between colorectal cancer and lignans commonly present in Western diets. Dietary lignan intake produced a significant reduction in colorectal cancer risk (53).

Few epidemiologic studies have been conducted on the relationship between phytoestrogens and colorectal polyps formation. A case-control study on the role of lignans (54) suggests that these compounds may be protective against cardiovascular diseases and polyps (55).

Our research group aimed to assess whether a specifically ERβ-targeted dietary management of human, recurrent sporadic adenopolyposis could have any impact on ERβcontrolled apoptosis and/or proliferative behavior. As a preliminary step, we assessed whether non adenomatous (normal) mucosa of patients affected by sporadic adenopolyposis displayed an impaired apoptotic control of cell proliferation, dependent upon a reduced ER-β expression similar to that observed in the ApcMin/+ mouse. We designed a randomized, double blind placebo-controlled study to further assess whether a proprietary blend of ER-β agonists (a mixture of silymarin, 30% of which as silibinin) could positively affect the ERβ-dependent apoptotic control of cell proliferation, in the normal mucosa of patients affected by sporadic adenopolyposis, prone to polyp recurrence, and enrolled in a surveillance program for the follow-up of polyp recurrence by screening colonoscopy every 3-5 years.

We also assessed urinary phytoestrogens to check for compliance to sylimarin supplementation, and to see whether biomarkers expression was differently related to the phytoestrogens from the regular diet as opposed to the supplements given during the study period, in the two study groups. All patients were instructed to maintain their regular diet over the study period. Urinary phytoestrogens (ng/mL), namely the active lignans: enterodiol (ED) and enterolactone (EL), were measured on spot urinary samples.

In this clinical trial, we similarly hypothesized a ERβ down-modulation, paving the way for an altered apoptotic control of cell proliferation, in the non adenomatous colon mucosa of patients affected by sporadic adenopolyposis, presenting with a similar cell proliferation rate. We found that the normal mucosa of an APC-mutated intestinal environment is prone to polyp development and recurrence because of an altered proliferation-apoptosis ratio, related to a decreased ER-β expression. Moreover, we demonstrated that ER-β dependent apoptosis can be restored by administering specific phytoestrogens supplements with a selective action on ERβ, in a similar manner to what we had previously observed in ApcMin/+ mice. This randomized, double-blind placebo-controlled study showed that sylimarin, lignans and lignin can positively affect the ERβ-driven apoptotic control of colon epithelial turnover, by increasing ER-β expression in the normal mucosa of sporadic adenopolyposis patients prone to polyp recurrence. This is achieved via an increased ERβ content and was demonstrated in all patients, regardless of whether they were free from polyps or not, at screening colonoscopy.

#### **7. References**

326 Cancer Prevention – From Mechanisms to Translational Benefits

of a combination of the ER-β-selective agonist silymarin and/or lignin to a high-fat/lowfiber diet, which has been shown to foster tumor growth. The addition of silymarin or lignin to the diet and, to an even greater extent, the specific combination of the two, significantly counteracted intestinal tumorigenesis and increased ER-β mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in wild type animals. These results further support a protective effect of ER-β in CRC, suggesting that dietary supplementation with the combination of silymarin and lignin could be a potential approach to CRC prevention

Several studies have reported a reduction of the CRC risk associated with the consumption of soy foods (the main source of isoflavones) and non-fermented soy foods (e.g. tofu) (47- 52). The main limitations of these studies are that they all assessed only specific soy foods intake rather than total phytoestrogen intake: none of the studies was designed to evaluate

Another study investigated the association between colorectal cancer and lignans commonly present in Western diets. Dietary lignan intake produced a significant reduction in colorectal

Few epidemiologic studies have been conducted on the relationship between phytoestrogens and colorectal polyps formation. A case-control study on the role of lignans (54) suggests that these compounds may be protective against cardiovascular diseases and

Our research group aimed to assess whether a specifically ERβ-targeted dietary management of human, recurrent sporadic adenopolyposis could have any impact on ERβcontrolled apoptosis and/or proliferative behavior. As a preliminary step, we assessed whether non adenomatous (normal) mucosa of patients affected by sporadic adenopolyposis displayed an impaired apoptotic control of cell proliferation, dependent upon a reduced ER-β expression similar to that observed in the ApcMin/+ mouse. We designed a randomized, double blind placebo-controlled study to further assess whether a proprietary blend of ER-β agonists (a mixture of silymarin, 30% of which as silibinin) could positively affect the ERβ-dependent apoptotic control of cell proliferation, in the normal mucosa of patients affected by sporadic adenopolyposis, prone to polyp recurrence, and enrolled in a surveillance program for the follow-up of polyp recurrence by screening

We also assessed urinary phytoestrogens to check for compliance to sylimarin supplementation, and to see whether biomarkers expression was differently related to the phytoestrogens from the regular diet as opposed to the supplements given during the study period, in the two study groups. All patients were instructed to maintain their regular diet over the study period. Urinary phytoestrogens (ng/mL), namely the active lignans:

In this clinical trial, we similarly hypothesized a ERβ down-modulation, paving the way for an altered apoptotic control of cell proliferation, in the non adenomatous colon mucosa of

enterodiol (ED) and enterolactone (EL), were measured on spot urinary samples.

(46).

**6. Phytoestrogens in human CRC** 

phytoestrogen intake.

colonoscopy every 3-5 years.

cancer risk (53).

polyps (55).


Phytoestrogens as Nutritional Modulators in Colon Cancer Prevention 329

[33] Polyak,S.J. et al. (2007) Inhibition of T-cell inflammatory cytokines, hepatocyte NF-

[34] Wuttke-Seidlova D, Becker T, Cristoffel V, Jarry H, Wuttke W (2003) Silymarin is a

[35] Agarwal R, Agarwal C, Ichikawa H, et al. 2006 Anticancer potential of silymarin: from

[36] Velmuragan B. et al. 2010 Silibinin exerts sustained growth suppressive effect against

[37] Wasilewiwicz M et al. 2010 Overexpression of 5-lipoxygenase in sporadic adenomas

[38] Begum A et al. 2004 Dietary lignins are precursors of mammalian lignans in rats. J

[39] Rajamanickam S, Agarwal R. 2008 Natural products and colon cancer: current status

[40] Kuijsten A, et al. 2006 Plasma enterolignans are associated with lower colorectal

[41] Touré A, Xueming X. 2010 Flaxseed lignans: source, biosynthesis, metabolism,

[42] Mueller S, Simon S, Chae K, et al. 2004 Phytoestrogens and their human metabolites

[43] Moser, A.R. et al. (1990) A dominant mutation that predisposes to multiple intestinal

[44] Javid, S.H. et al. (2005) Modulation of tumor formation and intestinal cell migration by

[45] Khono H et al. 2002 Silymarin, a naturally occurring polyphenolic antioxidant

[46] Michele Barone et al. (2010). Dietary-induced ERb upregulation counteracts intestinal

[47] Grodstein F et al. 1998. Postmenopausal hormone use and risk for colorectal cancer and

[48] Hoshiyama Y et al. (1993) A case-control study of colorectal cancer and its relation to

[49] Jacobson JS et al. 1996. Hormone replacement therapy is associated with lower risk of

unit case control study.Cancer Epidemiol Biomarkers Prev 5(10):779–784

adenoma risk. Cancer Epidemiol Biomarkers Prev;15:1132-1136.

ovariectomized rats.J Steroid Biochem Mol Biol 86(1):179–188

bench to bed side. Anticancer Res;26:4457-98.

and future prospects. Drug Dev Res;69:460-471.

and ERβ in Human Cells. Toxicol Sci;80: 14-25

neoplasia in the mouse. Science, 247, 322–324.

adenoma. Ann Intern Med 128(9):705–712

molecules. Pharm Res;27:2085-2097.

132, 1925–1936.

Nutr;134:120-12.

Food Safety;9:261-269

Int J Cancer 101(5):461–468

Exp Med 171(2):153–165

587–595.

pp.269–274

kappaB signaling, and HCVinfection by standardized Silymarin.Gastroenterology,

selective estrogen receptor beta (ER beta) agonist and has estrogenic effects in the metaphysis of the femur but no antiestrogenic effects in the uterus of

human colon carcinoma SW480 xenograft by targeting multiple signaling

and a possible new aspect of colon carcinogenesis. Int J Colorectal Dis;25:1079-1085.

antioxidant, bio-active components, and health benefits. Compreh Rev Food Sci

show distinct agonistic and antagonistic properties on Estrogen Receptor α (ERα)

estrogens in the ApcMin/þ mouse model of colorectal cancer. Carcinogenesis, 26,

flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats.

neoplasia development in intact male ApcMin/1 mice. Carcinogenesis vol.31 no.2

diet, cigarettes, and alcohol consumption in Saitama Prefecture, Japan. Tohoku J

adenomatous polyps of the large bowel: the Minnesota cancer prevention research


[15] Lindberg, M.K. et al. 2003 Estrogenreceptor(ER)-betareduces ERalpharegulated gene

[16] Gustafsson, J.A. (1999) Estrogen receptor b: a new dimension in estrogen mechanism of

[17] Giroux,V. et al. (2008) Estrogen receptor beta/deciency enhances small intestinal

[18] Kronenberg F, Fugh-Berman A (2002). Complementary and alternative medicine for

[19] Barone M, Tanzi S, Lofano K, et al. Dietary-induced ERβ upregulation counteracts

[20] Matsuda H, et al. 2001 Phytoestrogens from the roots of Polygonum

[21] Whitten PL, Naftolin F (1998) Reproductive actions of phytoestrogens.Baillieres Clin

[22] Adlercreutz H, Fotsis T, Heikkinen R, Dwyer JT, Goldin BR, Gorbach SL, Lawson AM,

[23] Adlercreutz H, Höckerstedt K, Bannwart C, Bloigu S, Ha¨ma¨la¨inen E, Fotsis T, Ollus A

[24] Otieno DO, Shah NP (2007) Endogenous beta-glucosidase and beta-galactosidase

[25] Kronenberg F, Fugh-Berman A (2002) Complementary and alternative medicine for

[26] Setchell KD (1998) Phytoestrogens: the biochemistry, physiology and implications for human health of soy isoflavones. Am J Clin Nutr 68(6 Suppl):1333s–1146s [27] Kuiper GGJM et al Lemmen JG, Carlsson B et al (1996) Interaction of estrogenic

[28] Anderson JJB, Anthony M, Messina M, Garner SC (1999) Effect of phytoestrogens on

[29] Adlercreutz H et al (2000) Food containing phytoestrogens, and breast cancer.

[30] Santti R, Makela S, Strauss L, Korkman J, Kostian ML (1998) Phytoestrogens: potential

[31] Messina MJ, Loprizi CL (2001) Soy for breast cancer survivors: a critical review of the

[32] Kurzer MS (2002) Hormonal effects of soy in premenopausal women and men. J Nutr

endocrine disruptors in males. Toxicol Ind Health 14(1–2):223–237

binding globulin (SHBG). J Steroid Biochem 27(4–6):1135–1344

biotransformation in soymilk.J Appl Microbiol 103(4):910–91

tumorigenesis in ApcMin/þ mice. Int. J. Cancer, 123,303–311.

in mice. Mol. Endocrinol., 17, 203–208.

activity. Bioorg Mol Chem Lett 11(14):1839–184

Endocrinol Metab 12(4):667–690

action. J. Endocrinol., 163, 379–383.

137(7):805–813

2010;31:269-274

Biol 59(4):259–261

137(7):805–813

139(10):4252–4263

132(3):570s–573s

Biofactors 12(1–4):89–93

tissues. Nutr Res Rev 12(3):75–116

literature. J Nutr 131(11 Suppl):3095s–3108s

transcription, supporting a ''ying yang'' relationship between ERalpha and ERbeta

menopausal symptoms. A review of randomized, controlled trials. Ann Intern Med

intestinal neoplasia development in intact male ApcMin/+ mice. Carcinogenesis

cuspidatum:structure requirement of hydroxyanthraquinones for estrogenic

Setchell KD (1981) Diet and urinary excretion of lignans in female subjects. Med

(1987) Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens and on sex hormone

activities from selected probiotic microorganisms and their role in isoflavone

menopausal symptoms. A review of randomized, controlled trials. Ann Intern Med

chemicals and phytoestrogens with estrogen receptor beta. Endocrinology


**13** 

*Uludag University* 

*Turkey* 

**The Therapeutic Potential of Pomegranate** 

**and Its Products for Prevention of Cancer** 

Pomegranate (*Punica granatum* L.) is considered one of the oldest known edible fruits and is the symbolic of abundance and prosperity. For thousand of years, many cultures have believed that pomegranate have beneficiary effects on health, fertility, longevity and rebirth. The recent interest for this fruit is not only because of the pleasant taste, but also due to the scientific evidences that suggest therapeutic activity such as anti-atherogenic, antiparasitic, antimicrobial, antioxidant, anticarcinogenic and antiinflammatory effects. These beneficial effects were attributed to the antioxidative properties of pomegranate phenolic compounds, tannins and anthocyanins as well as other phytochemicals. The constituents of pomegranate have been thoroughly investigated, however, clinical trials are in progress to explore the therapeutic potential of pomegranate products, particularly determining preventive efficacy of pomegranate extracts in cancer, cardiovascular diseases, inflammation, diabetes and ultraviolet radiation-induced skin damage. In order to facilitate the further investigations the information contained in this work is based upon the immense work on impact of administration of pomegranate extracts*,* particularly in cancer prevention such as skin,

Along with olives, figs and grapes, pomegranates are among the first plants to have been cultivated by man. Pomegranate (*Punica granatum* L.) is considered one of the oldest known edible fruit that is mentioned in the Koran, the Bible, the Jewish Torah, and the Babylonian Talmud as 'Food of Gods' that is symbolic of plentyness, fertility and prosperity (Madihassan, 1984; Aviram et al., 2000; Seeram et al., 2006). The pomegranate, a mystical and highly distinctive fruit, is the predominant member of two species comprising the *Punicaceae* family. The genus name Punica, was the Roman name for Carthage, where the best pomegranates were known to grow. Pomegranate is known by the French as grenade, the Spanish as granada (derived from the ancient city of Granada), and literally translates to

In ancient Greek mythology, the edible part of pomegranate known as the "fruit of the dead", containing considerable amounts of saccharides, polyphenol, and available in Hades for its residents. Hades benefitted amorously when six pomegranate seeds from his kingdom sealed for him the betrothal of the daughter of Zeus and Demeter. The

**2. The constituents of pomegranate and derived products** 

seeded ("granatus") apple ("ponium") (Jurenka, 2008).

**1. Introduction** 

prostate, breast, and colon.

Arzu Akpinar-Bayizit, Tulay Ozcan and Lutfiye Yilmaz-Ersan

