**1. Introduction**

284 Cancer Prevention – From Mechanisms to Translational Benefits

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the active component of St. John's wort, induces IL-8 expression in human intestinal epithelial cells via a MAPK-dependent, NF-kappaB-independent Given that there is a wealth of literature on the potential effect of a wide variety of phytochemicals on the growth of prostate cancer cells, we have limited our discussion to arguably four of the most important: isoflavones, lycopene, resveratrol, and curcumin. The focus of this review is on the clinical pharmacology of these compounds, as there are already an extensive number of reviews in the literature on all of these compounds for various cancers, including our previous review of isoflavones in prostate cancer (de Souza et al., 2009). Here, we use the loose term "phytochemicals" to describe this group of plant– based compounds with biological activity *in vitro,* for simplicity. Like other phytochemicals, isoflavones, lycopene, resveratrol and curcumin have a wide variety of potential mechanisms of action in many different cancer cell lines. Many of these biological effects involve key components of signal transduction pathways within cancer cells, but in this review, we will be focusing on studies specifically in prostate cancer.

Reactive oxidative species (ROS) may have an overall contribution to the development of cancer (Kryston et al., 2011; Benhar et al., 2002), but the mechanism is far from clear, though the general thrust of the argument is that DNA damage wrought by ROS may be left unchecked or uncorrected by mismatch repair enzymes, thereby contributing to carcinogenesis (Benhar et al., 2002, Ziech et al., 2010, Kryston et al., 2011). However, it is also apparent that higher levels of ROS can activate intrinsic apoptosis (Benhar et al., 2002), which would imply that antioxidants should not be used indiscriminately as it could prevent a desirable outcome in cancer cells. The biological mechanisms underpinning some of the potential anti-oxidant mechanisms of phytochemicals are complex and as yet speculative, and will not be discussed here. Instead, readers are referred to recent reviews (Ziech et al., 2010; Kryston et al., 2011).

<sup>\*</sup> Corresponding author

Dietary Manipulation for Therapeutic Effect in Prostate Cancer 287

flavonols, catechins, anthocyanins, and chalcones, of which the isoflavones are but a small part, though disproportionately studied. Isoflavone intake is approximately 50mg daily in

There are many intermediates and metabolites of isoflavones produced in humans, but the majority have not been studied. Genistin, daidzin and glycitin are thought to be the predominant isoflavones found in soy foods, of which the glycoside moiety is the major form with anticancer activity. Through the action of - glucosidase provided by gut bacteria, and hydrolysis, the conversion of glycosides to aglycones (Setchell et al., 2002; Yuan et al., 2007; Zubik & Meydani, 2003) allows absorption into the blood. One hypothesis for the variable absorption values obtained from studies is the variability of the gut microbacterial environment amongst humans. Some support for this concept was provided by Rufer et al., (2008), who gave pure daidzein in both its aglycone and glycoside forms to seven volunteer men in a randomized, double – blind study, at a dose of 1mg/kg. Bioavailability of the glycoside form was found to be 3-6 times higher than that of the aglycone form, with half – life measured at 6.4h for the glycoside and 8.9h for the aglycone. Given the differences recorded for maximum concentration (Cmax) and urinary excretion, it is not unreasonable to speculate that this observation could be explained by the time taken by gut microflora to generate metabolites. Inter - individual variability in pharmacokinetic parameters was very high for these metabolites, which clearly could not be explained by

differences in pharmacogenomic factors, due to the randomized crossover design.

There are few other pharmacokinetic reports of isoflavones and data are derived largely from single dose administration studies. In general, aglycones appear in the blood within two hours of ingestion (Atkinson et al., 2005; Franke et al., 1995; Richelle et al., 2002; Setchell et al., 2001). Peak plasma concentrations (Cmax) for aglycones occur at 4-7h, whereas the corresponding time for glycosides is 8-11h, implying that the rate limiting step for absorption is initial hydrolysis of the isoflavone (Setchell et al., 2001; Zubik & Meydani, 2003). After about 48hrs, plasma concentrations are no longer detectable. In a study reported by Setchell et al., (2003), higher doses of isoflavones did not produce linear pharmacokinetic parameters, suggesting that uptake was rate - limiting and saturable. Administration of approximately 80mg isoflavones a day is thought to give concentrations of genistein and daidzein consistent with that found in patients on a high isoflavone diet (Howes et al., 2002).

The literature attests to a large array of potential biological effects of isoflavones, despite their similarity in chemical structure: genistein binds estrogen receptor better than daidzein (Kuiper et al., 1998) for example, and equol is more potent than daidzein in inhibiting prostate cancer cell growth (Hedlund et al., 2003). Genistein produces apoptosis in prostate cancer cells (Kyle et al., 1997), but it is also possible that low doses promote cancer cell growth while higher doses inhibit growth (Bergan et al., 1996). This apparently conflicting data is not limited to isoflavones, and if the potential biphasic effects of phytochemicals are true, the underlying mechanisms for this observation could represent an important area of

Asia, about ten times more than in Western countries (Messina et al., 2006).

**2.1 Pharmacology** 

**2.2** *In vitro* **data** 

future research.

Table 1 lists the major sources of our selected phytochemicals (Holden et al., 1999; Neveu et al., 2010; Nutrient Data, L. & Knovel, 2008; Tayyem et al., 2009), though we acknowledge that many other foods contain smaller amounts as well, though they are not reviewed here.


Table 1. Dietary sources of selected phytochemicals.

#### **2. Isoflavones**

Soy and soy products, rye bread, and red clover, are good sources of flavonoids (Adlercreutz, 2002). Flavonoids, in turn, are made up of isoflavones, flavonones, flavones, flavonols, catechins, anthocyanins, and chalcones, of which the isoflavones are but a small part, though disproportionately studied. Isoflavone intake is approximately 50mg daily in Asia, about ten times more than in Western countries (Messina et al., 2006).

#### **2.1 Pharmacology**

286 Cancer Prevention – From Mechanisms to Translational Benefits

Table 1 lists the major sources of our selected phytochemicals (Holden et al., 1999; Neveu et al., 2010; Nutrient Data, L. & Knovel, 2008; Tayyem et al., 2009), though we acknowledge that many other foods contain smaller amounts as well, though they are not reviewed here.

> **Lycopene mg/100g**

Bilberry 0.67 Chocolate, dark 0.04

Grape, black 0.15

Lingonberry 3.00 Peanut 0.02 0.08 Peanut butter 0.01 0.04 Pistachio 3.6 0.11 Red currant 1.57

22.5

30.0

Strawberry 0.35

Wine, Red 0.27 Wine, Rose 0.12 Wine, White 0.04

Soy and soy products, rye bread, and red clover, are good sources of flavonoids (Adlercreutz, 2002). Flavonoids, in turn, are made up of isoflavones, flavonones, flavones,

17.0

Soy paste, miso 41.4

**Isoflavones mg/100g** 

1.92

**Resveratrol mg/100g** 

**Food Curcumin** 

Curry 50-580

Cranberries, European

Soybean, tofu,firm

silken

Soybean,tofu,

Tomato, sauce (ketsup)

**2. Isoflavones** 

Turmeric powder

**mg/100g** 

Apricots, tinned 0.065

Grapefruit, pink 1.3-1.5 Guava, fresh 5.4 Guava, juice 3.3

Tomato, raw 3.0 Tomato, boiled 4.4 Tomato juice 9.3 Tomato paste 6.5-29.3

Tomato, tinned 9.7

Table 1. Dietary sources of selected phytochemicals.

580-3,140

There are many intermediates and metabolites of isoflavones produced in humans, but the majority have not been studied. Genistin, daidzin and glycitin are thought to be the predominant isoflavones found in soy foods, of which the glycoside moiety is the major form with anticancer activity. Through the action of - glucosidase provided by gut bacteria, and hydrolysis, the conversion of glycosides to aglycones (Setchell et al., 2002; Yuan et al., 2007; Zubik & Meydani, 2003) allows absorption into the blood. One hypothesis for the variable absorption values obtained from studies is the variability of the gut microbacterial environment amongst humans. Some support for this concept was provided by Rufer et al., (2008), who gave pure daidzein in both its aglycone and glycoside forms to seven volunteer men in a randomized, double – blind study, at a dose of 1mg/kg. Bioavailability of the glycoside form was found to be 3-6 times higher than that of the aglycone form, with half – life measured at 6.4h for the glycoside and 8.9h for the aglycone. Given the differences recorded for maximum concentration (Cmax) and urinary excretion, it is not unreasonable to speculate that this observation could be explained by the time taken by gut microflora to generate metabolites. Inter - individual variability in pharmacokinetic parameters was very high for these metabolites, which clearly could not be explained by differences in pharmacogenomic factors, due to the randomized crossover design.

There are few other pharmacokinetic reports of isoflavones and data are derived largely from single dose administration studies. In general, aglycones appear in the blood within two hours of ingestion (Atkinson et al., 2005; Franke et al., 1995; Richelle et al., 2002; Setchell et al., 2001). Peak plasma concentrations (Cmax) for aglycones occur at 4-7h, whereas the corresponding time for glycosides is 8-11h, implying that the rate limiting step for absorption is initial hydrolysis of the isoflavone (Setchell et al., 2001; Zubik & Meydani, 2003). After about 48hrs, plasma concentrations are no longer detectable. In a study reported by Setchell et al., (2003), higher doses of isoflavones did not produce linear pharmacokinetic parameters, suggesting that uptake was rate - limiting and saturable. Administration of approximately 80mg isoflavones a day is thought to give concentrations of genistein and daidzein consistent with that found in patients on a high isoflavone diet (Howes et al., 2002).

#### **2.2** *In vitro* **data**

The literature attests to a large array of potential biological effects of isoflavones, despite their similarity in chemical structure: genistein binds estrogen receptor better than daidzein (Kuiper et al., 1998) for example, and equol is more potent than daidzein in inhibiting prostate cancer cell growth (Hedlund et al., 2003). Genistein produces apoptosis in prostate cancer cells (Kyle et al., 1997), but it is also possible that low doses promote cancer cell growth while higher doses inhibit growth (Bergan et al., 1996). This apparently conflicting data is not limited to isoflavones, and if the potential biphasic effects of phytochemicals are true, the underlying mechanisms for this observation could represent an important area of future research.

Dietary Manipulation for Therapeutic Effect in Prostate Cancer 289

a. Prostate androgen regulated transcript 1 inhibited by genistein and daidzein

d. Curcumin downregulates AR gene expression in androgen dependent and castration resistant prostate

a. mRNA expression and secretion reduced by genistein

downregulated by lycopene in

c. Resveratrol downregulates expression in LNCaP cells d. Curcumin inhibits PSA

b. Lycopene reduces DNA synthesis in primary cultures

a. Cyclin B downregulated by

b. Lycopene downregulates

c. C1/Cdk4 kinase and D1, E, B and cdk1 all downregulated by resveratrol in LNCaP lines; resveratrol increases cyclin A and cyclin E in LNCaP cells d. Curcumin downregulates

of prostate epithelia

cyclin expression

Wee-1 a. Phosphorylation reduced by

LNCaP

Myt-1 a. Upregulated by genistein a. (Touny & Banerjee, 2006)

a. Upregulated by genistein c. Decreased by resveratrol in

d. Upregulated by curcumin

genistein a. (Touny & Banerjee, 2006)

1998)

b. PSA mRNA not

5α reductase a. Inhibited by genistein a. (Evans et al., 1995)

a. Transcriptionally downregulated by genistein b. In LNCaP cells, Lycopene inhibited AR gene element in a dose response manner c. Resveratrol inhibits AR transcription activity in

LNCaP

cancer cells

LNCaP

expression

genistein

cyclin D1

**Androgen related functions**

PART-1

AR

PSA

**Cell survival and proliferation**

DNA synthesis

Cyclins

p21WAF1

**Action References** 

a. (Yu et al., 2003)

et al., 2008)

2007)

et al., 1999) d. (Tsui et al., 2008)

a. (Davis et al., 2000; Takahashi et al., 2006; Tepper et al., 2007) b. (Zhang et al., 2010) c. (Wang et al, 2010)

d. (Nakamura et al, 2002; Tsui

a. (Davis et al., 2000; Rice et al.,

b. (Peternac et al., 2008) c. (Hsieh & Wu, 2000; Mitchell

b. (Barber et al, 2006)

a. (Davis et al., 1998) b. (Palozza et al., 2010) c. (Benitez et al., 2007; Kuwajerwala et al., 2002) d. (Aggarwal et al., 2009)

a. (Davis et al., 1998; Lian et al.,

c. (Benitez et al., 2007; Kuwajerwala et al., 2002; Mitchell et al., 1999) d. (Aggarwal et al., 2007)

Tyrosine kinase phosphorylation appears to be a key event influencing the fate of many cancer cells, and inhibition may increase apoptosis or inhibit prostate cancer cell growth. Some isoflavones appear to have this ability; for example, genistein has been shown to reduce FAK (focal adhesion kinase) activity just prior to apoptosis (Kyle et al., 1997). It can also transiently activate the FAK : beta – 1 – integrin complex (Bergan et al., 1996; Liu et al., 2000), which could theoretically help explain its ability to reduce metastases. Further, isoflavones may reduce activity of ERK1/2 and various cyclin dependent kinases (Agarwal et al., 2000). A range of other potential mechanisms for the growth inhibiting effects of isoflavones have been described (see Table 2).

#### **2.3** *In vivo* **data**

Soy protein or biochanin A (another isoflavone) inhibits growth and increases apoptosis in the LNCaP prostate cancer xenograft model (Bylund et al., 2000; Rice et al., 2002). Dietary genistein supplementation can reduce the incidence of poorly differentiated adenocarcinoma in a transgenic strain of mice (Mentor-Marcel et al., 2001), and can improve survival. In a model where prostate cancer is induced by chemical carcinogens methyl nitrosourea (NMU) or 3,2-dimethyl-4-aminobiphenyl (DMAB) (Kato et al., 2000), soy protein or genistein can prevent growth (McCormick et al., 2007; Wang et al., 2002). Dose - response studies involving subcutaneously and orthotopically implanted tumours (Zhou et al., 1999; 2002) demonstrated clear reduction of tumor growth with a variety of isoflavone preparations, though changes in a variety of biomarkers were not consistent, and depended on the type of isoflavone preparation.

#### **2.4 Clinical studies in prostate cancer**

An interesting study of 40 men randomized post-prostatectomy to a low fat / high isoflavone diet (Li et al., 2008) or a control diet showed lower 6 month IGF-1 concentrations in the treatment group. Sera collected from treated patients were able to reduce *in vitro* growth of LNCaP cancer cells by 20%, suggesting biologically relevant concentrations were achieved. Soy has been shown to suppress growth of localized, but not for advanced disease (Kurahashi et al., 2007), perhaps not surprisingly, since prostate cancer is a heterogenous disease, and more advanced disease may have different underlying biology. Pharmacogenomic work suggests that the reduction in risk of prostate cancer may be positively associated with a greater ability to produce equol from other isoflavones (Akaza et al., 2002, 2004). "Nutrigenomic" factors may therefore play an important part in predicting those who might benefit from phytoestrogen supplementation (Steiner et al, 2008).

Many studies do not show evidence of benefit for isoflavones. One randomized, placebocontrolled trial of 12 weeks treatment with genistein in men with early prostate cancer found no significant difference in PSA levels between the treatment and placebo groups (Kumar et al., 2004), although the authors suggested that surrogate measures were being affected by treatment. Other trials support the idea that isoflavones, even given over relatively short periods of time, can possibly slow the rate of rise of PSA, though no statistically significant conclusions can be drawn (Dalais et al., 2004; Hussain et al., 2003; Maskarinec et al., 2006; Pendleton et al., 2008). Even by administering high doses, up to 600mg genistein daily, no statistically significant PSA changes were noted in a Phase I and

Tyrosine kinase phosphorylation appears to be a key event influencing the fate of many cancer cells, and inhibition may increase apoptosis or inhibit prostate cancer cell growth. Some isoflavones appear to have this ability; for example, genistein has been shown to reduce FAK (focal adhesion kinase) activity just prior to apoptosis (Kyle et al., 1997). It can also transiently activate the FAK : beta – 1 – integrin complex (Bergan et al., 1996; Liu et al., 2000), which could theoretically help explain its ability to reduce metastases. Further, isoflavones may reduce activity of ERK1/2 and various cyclin dependent kinases (Agarwal et al., 2000). A range of other potential mechanisms for the growth inhibiting effects of

Soy protein or biochanin A (another isoflavone) inhibits growth and increases apoptosis in the LNCaP prostate cancer xenograft model (Bylund et al., 2000; Rice et al., 2002). Dietary genistein supplementation can reduce the incidence of poorly differentiated adenocarcinoma in a transgenic strain of mice (Mentor-Marcel et al., 2001), and can improve survival. In a model where prostate cancer is induced by chemical carcinogens methyl nitrosourea (NMU) or 3,2-dimethyl-4-aminobiphenyl (DMAB) (Kato et al., 2000), soy protein or genistein can prevent growth (McCormick et al., 2007; Wang et al., 2002). Dose - response studies involving subcutaneously and orthotopically implanted tumours (Zhou et al., 1999; 2002) demonstrated clear reduction of tumor growth with a variety of isoflavone preparations, though changes in a variety of biomarkers were not consistent, and depended

An interesting study of 40 men randomized post-prostatectomy to a low fat / high isoflavone diet (Li et al., 2008) or a control diet showed lower 6 month IGF-1 concentrations in the treatment group. Sera collected from treated patients were able to reduce *in vitro* growth of LNCaP cancer cells by 20%, suggesting biologically relevant concentrations were achieved. Soy has been shown to suppress growth of localized, but not for advanced disease (Kurahashi et al., 2007), perhaps not surprisingly, since prostate cancer is a heterogenous disease, and more advanced disease may have different underlying biology. Pharmacogenomic work suggests that the reduction in risk of prostate cancer may be positively associated with a greater ability to produce equol from other isoflavones (Akaza et al., 2002, 2004). "Nutrigenomic" factors may therefore play an important part in predicting those who might benefit from phytoestrogen supplementation (Steiner et al,

Many studies do not show evidence of benefit for isoflavones. One randomized, placebocontrolled trial of 12 weeks treatment with genistein in men with early prostate cancer found no significant difference in PSA levels between the treatment and placebo groups (Kumar et al., 2004), although the authors suggested that surrogate measures were being affected by treatment. Other trials support the idea that isoflavones, even given over relatively short periods of time, can possibly slow the rate of rise of PSA, though no statistically significant conclusions can be drawn (Dalais et al., 2004; Hussain et al., 2003; Maskarinec et al., 2006; Pendleton et al., 2008). Even by administering high doses, up to 600mg genistein daily, no statistically significant PSA changes were noted in a Phase I and

isoflavones have been described (see Table 2).

on the type of isoflavone preparation.

**2.4 Clinical studies in prostate cancer** 

**2.3** *In vivo* **data** 

2008).


Dietary Manipulation for Therapeutic Effect in Prostate Cancer 291

a. (Pinski et al., 2006) c. (Sallman et al., 2007) d. (Lin et al., 2009)

a. (Xu & Bergan, 2006) d. (Park et al., 2003)

a. (Li et al., 2005) d. (Li et al., 2007)

a. (Kazi et al., 2003) b. (Palozza et al., 2010) c. (Benitez et al., 2007)

a. (Li et al., 2001)

2004)

d. (Shankar & Srivastava, 2007)

d. (Shankar & Srivastava, 2007)

a. (Alvero et al., 2006; Herst et al., 2007; Kamsteeg et al., 2003, Kluger et al., 2007; Sapi et al.,

c. (Gogada et al., 2011) d. (Deeb et al., 2007)

a. (Aguero et al., 2005; Choueiri et al., 2006; Kumi-Diaka et al., 2000; Kumi-Diaka

(Shankar & Srivastava, 2007)

& Butler, 2000) c. (Benitez et al., 2007) d. (Hilchie et al., 2010) PC-3

LNCaP results

a. (Singh-Gupta, 2009) d. (Thomas et al, 2008)

results,

a. Activated by genistein c. Resveratrol inhibits Src and

d. STAT 3 is inhibited by curcumin, but even more so by synthetic analogues of

a. TGFβ inhibited by genistein d. IL6 induction via TGFβ inhibited via curcumin

a. Downregulated by genistein

Curcumin in a dose dependent

c. Increased due to resveratrol

a. Downregulated by genistein d. Down regulated by

a. Inhibited by phenoxodiol in ovarian cancer cells and melanoma cells c. Resveratrol promotes interaction of XIAP with Bax to

d. mRNA reduced by

a. Increased by genistein b. Lycopene upregulates Bax

d. Curcumin upregulates

Jak kinases

curcumin

manner

in LNCaP

in LNCaP

curcumin

cause apoptosis

apoptosis

d. Inhibited by curcumin

a. Activated and caspase inhibition overcome by phenoxodiol in HN12 cells; Caspase mediation by genistein induced apoptosis c. Resveratrol activates caspase: 9,6,7 and 3 leading to

d. In PC-3 cells, apoptosis caused by curcumin is independent of caspases; In LNCaP curcumin initiates caspase-dependent mitochondrial death

a. Inhibition by genistein in

d. Curcumin inhibits gene transcription of HIF 1 alpha

PC3 cancer cells

STAT

TGFβ

**Apoptosis**

Mdm2

Bax

Bcl-XL

XIAP

Caspases

**Other targets**

HIF1α


a. (Bhatia & Agarwal, 2001; Kazi et al., 2003; Rice et al.,

c. (Benitez et al., 2007; Kuwajerwala et al., 2002) d. (Aggarwal et al., 2007)

a. (Akiyama et al., 1987) c. (Sallman et al., 2007) d. (Dorai et al., 2000)

a. (Cao et al., 2006)

a. (Bemis et al., 2004; Li & Sarkar, 2002; El Touny & Banerjee, 2007; Park et al.,

b. (Ivanov et al., 2007)

Srivastava, 2007)

a. (Rice et al., 2007)

d. (Yu et al., 2008)

Bergan, 2006)

c. (Aziz et al., 2006; Chen et al.,

d. (Yu et al., 2008; Shankar &

c. (Brito et al, 2009; Chen et al.,

a. (Huang et al., 2005; Xu &

a. (Agarwal, 2000; Bhatia & Agarwal, 2001; Wang et al., 2006; Wang et al., 2004)

a. (Lazarevic et al., 2008) d. (Hilchie et al., 2010)

a. (Davis et al., 1999; Li & Sarkar, 2002; Raffoul et al., 2007; Singh-Gupta et al., 2009) b. ( Benitez et al., 2009)

a. (Takahashi et al., 2006, Wang et al., 2003) b. (Kanagaraj et al., 2007)

b. (Palozza et al., 2010) c. (Nguyen et al., 2008) d. (Hilchie et al., 2010)

2007)

2005)

2010)

2010)

a. Increased by genistein c. Upregulated by resveratrol in LNCaP only, not in PC-3 cells; repressed by resveratrol

d. Upregulated by curcumin

a. Inhibition of EGF tyrosine kinase activation by genistein c. Resveratrol inhibits tyrosine

d. Curcumin inhibits EGF-R

a.Expression is induced by genistein and daidzein in PC3

a. Inhibited by genistein b. Lycopene decreases AKT activation, leading to apoptosis in both androgen-responsive and independent PCa cells c. Inhibited by resveratrol d. Inhibited by curcumin; PI3K inhibited by curcumin

a. Inhibited by genistein c. Resveratrol inhibits mTOR d. Inhibited by curcumin in

a. MAPK inhibited by

c. MAPK is inhibited by

a. Inhibited by genistein; induced by isoflavones

d. Activated by curcumin

a. Inhibition by genistein b. Lycopene decreases IGF-1R expression in PC-3 cells

soy isoflavones b. Downregulated by

resveratrol

a. Inhibited by genistein and

d. P38 is activated by curcumin in PC3 cells

b. Lycopene, at least partially

PC-3 cells,

genistein

inhibits MAPK

resveratrol

JNK a. Activation by genistein

in LNCaP cells

kinase

signaling

and LNCaP

p27Kip1

PTEN

Akt

mTOR

MAPK

ERK1/2

NFκB

IGF-1/R

Protein tyrosine kinase


Dietary Manipulation for Therapeutic Effect in Prostate Cancer 293

Once water is reduced, the lycopene content of tomato products surpasses all other foods, weight for weight. Although lycopene melts at 172-173 degrees Celsius (Zapalis & Beck, 1985), processing and cooking improves availability of tomato-sourced lycopene. Being fat soluble, tomato sources of lycopene are best absorbed when cooked or consumed with a fat, such as with olive oil in Mediterranean cooking (Itsiopoulos et al., 2009). As lycopene synthesis correlates with tomato ripening, it is older, vine ripened-in-the sun tomatoes that offer the highest lycopene content (Ronen et al., 1999). Other sources of lycopene, in descending order of content are: guava, watermelon, pink grapefruit (Mangels et al., 1993),

Lycopene is a non-provitamin A carotenoid. The frequency of light absorption, due to its alternating double bond system, defines visual color ranging from pink through to deep red. Once consumed, lycopene micelles are believed to be formed by bile salts and along with fat, pass from the mucosa and into general circulation via low-density lipoproteins (Sharma & Goswami, 2011). It is the only carotenoid associated with plasma cholesterol level (Campbell et al., 1994). Within the body, lycopene is preferentially stored in the liver, seminal vesicles and the prostate tissue. In particular it becomes localized to the nuclear membrane and the nuclear matrix, suggesting that it may have a receptor or transporter role. In Western populations, blood lycopene concentrations range from 0.29-0.60 uM, with

A Phase I single-dose study on lycopene pharmacokinetics using increasing doses from 10 to 120 mg found dose dependent half-lives between 28 and 62 hours. Lycopene peaks

Like other phytochemicals, many potential mechanisms of action have been put forward to explain the anticancer properties of lycopene. Of relevance to prostate cancer, lycopene has been shown to inhibit DNA synthesis (Barber et al., 2006). Lycopene also inhibits growth of hormone-dependent LNCaP and C4-2 prostate cancer cell lines without affecting PSA mRNA expression (Peternac et al., 2008), and increases expression of PPARgamma and LXRalpha in LNCaP cells (Yang et al., 2011). It also inactivates Ras and reduces NFkappaB, as well as inducing apoptosis in LNCaP cells (Palozza et al., 2010). While it can reduce Akt activation (Ivanov et al., 2007), its ability to induce apoptosis may be cell line-dependent. Other potential mechanisms of action by lycopene in prostate cancer are listed in Table 2.

In combination with docetaxel, lycopene inhibits growth of hormone independent prostate cancer DU145 cells through insulin-like growth factor 1 receptors leading to downstream

Almost certainly, variations in experimental conditions, doses and techniques could contribute to these apparent biological effects. At physiological concentrations, however, lycopene may not have growth inhibitory effects on a variety of cell lines (Burgess et al., 2008). This was confirmed recently in experiments where supraphysiological concentrations

inhibition of survivin expression and subsequent apoptosis (Tang et al., 2011).

between 16 and 33 hours after dosing levels of 0.075 to 0.21 uM (Gustin et al., 2004).

apricots (Curl, 1960) and rosehips (Böhm et al., 2003).

a half-life of 2-3 days (Schwedhelm et al., 2003).

**3. Lycopene** 

**3.1 Pharmacology** 

**3.2** *In vitro* **data** 


Table 2. Selected molecular targets of phytochemicals in prostate cancer cells: (a), (b), (c), (d) refer to isoflavone, lycopene, resveratrol, and curcumin related literature, respectively. While many of these targets have been shown to be relevant in other cancer cell lines, here we have focused on publications on prostate cancer cell lines.

pharmacokinetic study (Fischer et al., 2004), though serum dehydroepiandrosterone was reduced by 31.7% (P = 0.0004) at the end of the study, and estrogenic side effects were encountered. Biologically relevant concentrations of genistein, commensurate with *in vitro*  activity, can be achieved with high doses of genistein - enriched isoflavone extracts (Takimoto et al., 2003). Peak plasma concentrations reached between 4.3 and 16.3uM at doses up to 8mg/kg orally (equivalent to 560mg for a 70kg person) in this study.
