**3.1 Pharmacology**

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

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

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

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

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

Dietary Manipulation for Therapeutic Effect in Prostate Cancer 295

consecutive men with hormone refractory prostate cancer treated with lycopene 10mg daily had shown a response rate (complete and partial) of 35% (Ansari et al., 2004). However, this phenomenal response rate has not been able to be repeated. Indeed, Vaishampayan et al., (2007) reported a study in 38 men with hormone sensitive and resistant cancer randomized to the lycopene alone arm and found only PSA stabilization, without any patient qualifying for a partial response. Adding soy isoflavones (to men randomized to the other arm) did not appear to improve outcome. Another study in 46 patients with androgen-independent prostate cancer prescribed 15mg lycopene daily found only one patient with a PSA response; toxicity included mainly grade 1-2 diarrhea, nausea, flatulence, and abdominal

Resveratrol is a phytoalexin found in the skins and seeds of red grapes V*itaceaea vinifera.* Therefore, red wines are especially rich in resveratrol, as is grape juice (Romero-Perez, 1999). Other sources include lentils (as resveratrol-3-O-glucoside), peanuts, dark chocolate and

Resveratrol is well-absorbed, but has poor bioavailability due to extensive first pass

A pharmacokinetic study of trans-resveratrol (25, 50, 100 or 150mg single doses, repeated over 13 dosings) showed Cmax detected 48 to 90 minutes post-dosing (Almeida et al., 2009), but there was wide interindividual variability reported, also noted in another pharmacokinetic study (Nunes et al., 2009). In another study in 40 healthy volunteers given a single dose ten times the quantities used in the previous study (500, 1000, 2,500 or 5,000mg), peak plasma concentrations were achieved in 90 minutes, and were associated with a range of plasma resveratrol concentrations between 73 and 539 ng/mL (Boocock et al., 2007). Absorption may be faster after oral dosing (Goldberg et al., 2003), possibly due to

Resveratrol is rapidly metabolized. Radioactively labeled carbon-14 distribution studies (Vitrac et al., 2003) have been performed in mice with trans-resveratrol; it distributes to the stomach, intestines, liver and kidney, regions of highest uptakes. Mice, like men (de Santi et al., 2000 a,b,c) also form both sulfur and glucuronide conjugates, but a proportion remains unchanged as trans-resveratrol. A toxicological study with trans-resveratrol (as resVida®) in rats over 4 weeks has tested up to 300 mg/kg/d, with no observed serious adverse events

A phase I trial and repeated dose study to determine safety, pharmacokinetics and the effect on insulin-like growth factor (IGF) axis by resveratrol was recently reported (Brown et al., 2010). Doses of 0.5, 2.5 or 5.0 g per day over 29 days was given to forty volunteers. Levels of resveratrol metabolites in plasma were about 20 times higher than that of free resveratrol, and a reduction of circulating plasma IGF-1 and IGFBP-3 was noted (P< 0.04 in both). It is not clear to what extent the metabolites contributed to the fall in plasma IGF-1 and IGFBP-3

distension (Jatoi et al., 2007).

**4. Resveratrol** 

berries (Neveu, 2010).

**4.1 Pharmacology** 

metabolism by the liver.

(Edwards et al., 2011).

levels.

delayed absorption by food (Vaz-da-Silva et al., 2008).

were required to reduce growth, possibly through alterations in the cell cycle (Ford et al., 2011).

### **3.3** *In vivo* **data**

Athymic mice models used by Yang et al., (2011) show strong inhibition of PC3 xenograft growth by high doses of lycopene (16 mg/kg), possibly via increased levels of insulin-like growth factor-binding protein 3, or a reduction in plasma vascular endothelial growth factor (VEGF) levels. In a provocative study of androgen expressing prostate cancer cell lines treated with serum from rats fed a control diet, or diets supplemented with red, or yellow tomato (containing no lycopene), connexin43 (a protein regulating cell growth) was upregulated by both the red and yellow tomato supplemented diet (Gitenay et al., 2007). This suggests tomato compounds other than lycopene may have a role in reducing prostate cancer cell growth; one such candidate might be FruHis, a carbohydrate derivative found in tomato products (Mossine et al., 2008). However, in humans at least, dietary lycopene has been shown to affect gene expression, regardless of whether it is included in its food matrix (Talvas et al., 2010)

In a transgenic mouse model, early intervention with selenium, vitamin E and lycopene supplements was able to significantly reduce prostate cancer and liver metastases (Venkateswaran et al, 2009). Limpens et al., (2006) had earlier reached the same conclusion, but they did not see any activity from the single agents. Naturally, it is difficult to know how much the additional supplements contributed to prostate cancer control, though both groups suggest the combination was important. Not all data are supportive of the growth inhibitory effect of lycopene however, possibly because of differences in the rat model used by Imaida et al., (2001).
