**5. Curcumin**

Curcumin is only found as an active component of whole or ground turmeric, within the rhizome or root nodule, specifically of two branches of the ginger family, Zingiberaceas, of the species, *Curcuma longa* Linneas, *Curcuma aromatica* or *Curcuma zantorrhiza* and in tropical ginger, *Zingiber cassumaunar*. In India, turmeric in dried curry powders range considerably from 10 to 32% (Govindarajan, 1980).

#### **5.1 Pharmacology**

Structurally, curcumin (diferuloylmethane, a polyphenolic molecule) is a diketone and can also be classified as a phenylpropanoid. It is known to have poor solubility and poor bioavailability (Anand et al., 2007). Absorption and transformation occurs at the intestinal wall, where enzymes such as sulfotransferases, UDP-glucoronyltransferase, and P450 ensure its rapid breakdown (Ireson et al., 2002). Pharmacokinetic studies, including Phase I and other trials confirm the poor bioavailability of the compound (Cheng et al, 2001; Sharma et al., 2004; Garcea et al., 2005; Garcea et al., 2004). Data from these studies show that curcumin seems to be absorbed from the gut within 1-2hrs, and doses up to 8000mg have produced minimal toxicity. Nausea and diarrhea have been the principal toxicities encountered. Vareed et al (2008) studied doses of either 10g or 12g in volunteers, and found Cmax to be around 1.7-2.3 ug/mL, with time taken to reach maximum concentration (Tmax) and halflife estimated to be 3.3h and 6.8h, respectively. Sharma et al., (2004) studied escalating doses in a Phase I trial up to 3.6g daily and found no dose-limiting toxicity. Mild nausea and diarrhea was encountered, but plasma concentrations of only around 10nM could be elicited in this study; nevertheless, inducible PGE2 production was reduced by about 50-60% at that dose level.

### **5.2** *In vitro* **data**

300 Cancer Prevention – From Mechanisms to Translational Benefits

Phase I Mild and reversible AEs (Elliott et al.,

and plasma

excretion.

achieved

daily

placebo

and pharmacodynamic variability, and other factors such as drug interaction. For example, resveratrol has been shown to inhibit cytochrome P 450; 3A4, 2D6, 2C9 and alternately induce 1A2 (Chow et al., 2010), a key factor that has not been taken into account in many clinical studies. Theoretically, interactions with concomitant medications whilst on trial may

Curcumin is only found as an active component of whole or ground turmeric, within the rhizome or root nodule, specifically of two branches of the ginger family, Zingiberaceas, of the species, *Curcuma longa* Linneas, *Curcuma aromatica* or *Curcuma zantorrhiza* and in tropical ginger, *Zingiber cassumaunar*. In India, turmeric in dried curry powders range considerably

Structurally, curcumin (diferuloylmethane, a polyphenolic molecule) is a diketone and can also be classified as a phenylpropanoid. It is known to have poor solubility and poor

therefore result in either unwanted toxicity or reduced concentrations of resveratrol.

6 metabolites found in urine

No serious adverse events Peak Plasma 539 ng/mL 1.5 hour post dose, peak AUC for metabolites were up to 23 time that of resveratrol, rapid urinary

No evidence of saturation with a continuing linear responsevery limited plasma concentrations, at high 5 g intake only 500 ng/mL levels

Lower IGF-1 and IGFBP-3 in plasma.In all ,28/40 healthy adults had at least one adverse event,: nausea, diarrhea or abdominal pain, all above 1 g

PSA reduction was greater in subgroup of men who had higher baseline PSA value, but overall, there was no statistical difference between those who had supplements and those on

2009)

2007)

(Boocock et al.,

(Boocock et al., 2007a,b)

(Brown et al., 2010)

(Ide et al., 2010)

Intervention / Diet Design Outcome Reference

N = Healthy volunteers

Healthy volunteers 10/level = 40

Pharmacokinetic study and metabolite

40 Healthy volunteers

 Healthy adults 22 Males, 18 Females

Pharmacokinetics

Randomised trial, N=85 men who had previous prostate biopsies but were negative for cancer

Table 3. Selected clinical trials of phytochemicals in prostate cancer.

2.5 versus 5 g per day for

Single resveratrol doses of 0.5, 1, 2.5 and 5 g using

500 mg caps resveratrol At 0.5, 1, 1.25 or 5.0 g once daily over 29 days

Soy isoflavones (40mg) + Curcumin (100mg) or placebo for 6 months

**Curcumin** 

**5. Curcumin** 

**5.1 Pharmacology** 

from 10 to 32% (Govindarajan, 1980).

25mg to 5 g resveratrol Dose escalation

Phase I

Safety,

Phase I

and PIN.

500 mg capsules

28 days

There is a wealth of literature on the potential mechanism of action of curcumin *in vitro* (see Table 2), but it is not clear which is the predominant mode of action. It is highly likely that different mechanisms of action exist for different cell lines. Curcumin can inhibit Akt and mTOR in PC3 cell lines (Yu et al., 2008), and enhance Apo2L/TRAIL induced apoptosis, at least in ovarian cancer cells (Wahl et al., 2007). EF24, a curcumin analogue, and curcumin itself can inhibit HIF1alpha gene transcription in PC3 prostate cancer cells (Thomas et al., 2008). Teiten et al., (2011) showed that curcumin induced cell cycle arrest in G2 phase and could modulate Wnt signaling in androgen-dependent prostate cancer cells, but not in androgen-independent cells.

Apoptotic and growth inhibitory pathways are affected by curcumin in numerous ways (Ravindran et al., 2009). One example is its ability to abrogate survival mechanisms via suppression of constitutive and inducible NF-kappaB activation (Mukhopadhyay et al., 2001). It can also induce apoptosis of DU145 and LNCaP, associated with reduction of expression of Bcl2 and bcl-xL (Mukhopadhyay et al., 2001).

#### **5.3** *In vivo* **data**

Curcumin inhibits LNCaP xenograft growth, induces apoptosis, and sensitizes tumours to TRAIL induced apoptosis (Shankar et al., 2007). Others have also demonstrated the growth inhibitory properties of curcumin *in vivo* (Barve et al., 2008; Khor et al., 2006), possibly via antiangiogenic mechanisms such as reduction of MMP-2 and MMP-9 expression (Hong et al., 2006). Liposomal encapsulation of curcumin, particularly in combination with resveratrol, significantly reduces prostate cancer tumours *in vivo* (Narayanan et al., 2009).

#### **5.4 Clinical studies**

Despite the intense interest in curcumin as a possible cancer prevention agent, there is a surprising lack of clinical data in prostate cancer. Efforts have focused on improving bioavailability by incorporating curcumin in nanoparticles, or developing more potent analogues. Whilst ongoing trials in prostate cancer are yet to be reported, the only trial we

Dietary Manipulation for Therapeutic Effect in Prostate Cancer 303

cisplatin has been shown to be synergistic against DU145 cells and probably additive in PC3 cells (McPherson et al., 2009). *In vivo* combination therapy of soy isoflavones and radiation for prostate cancer has also been investigated, with favorable effects on the control of the

Docetaxel effect in castration-resistant prostate cancer patients was improved by lycopene via insulin-like growth factor 1 receptor perturbation (Tang et al., 2011). Using an animal model to confirm these findings, a 38% improvement over docetaxel was found (P=0.047). Lycopene appeared to work by inhibiting IGF-1 stimulation and increasing expression and secretion of IGF-BP3. Downstream effects included reduced AKT kinase activity and

Resveratrol enhances ionizing radiation - induced cell death in DU145 cells, which are thought to be relatively radiation-resistant (Scarlatti et al., 2007), and as previously noted, enhances TRAIL-induced apoptosis *in vivo* (Ganapathy et al., 2010). Radiosensitisation properties, at least in PC3 cells, also appear to belong to curcumin (Chendil et al., 2004; Li et al., 2007), and like resveratrol, curcumin also enhances TRAIL-induced apoptosis in prostate cancer cells (Deeb et al., 2005). Synergy between curcumin and a number of cytotoxic agents including doxorubicin, 5FU and paclitaxel occurs in PC3 and DU145 cells (Hour et al., 2002),

The advantage of finding synergy lies in an increased benefit: risk ratio if compounds being combined are more effective (synergistic) without necessarily being more toxic, particularly if they are known to be well-tolerated as single agents. Further, because some phytochemicals have poor bioavailability, the discovery of synergistic interactions with other phytochemicals in prostate cancer gives rise to the hypothesis that therapeutic effects may be obtained from a variety of combinations, even though individual phytochemicals

The literature surrounding the idea of using phytochemicals for the prevention of prostate cancer is considerable, yet there are disproportionately few clinical studies, and just about none that show a convincing effect for biological outcomes in a clinical setting. Showing meaningful outcomes in a prostate cancer prevention trial with phytochemicals would ideally involve a prospective, randomized, placebo controlled trial that would require large numbers of patients to provide statistical power. Given that prostate cancer patients can live for many years, long-term follow up, is also required. Both of these requirements make such studies extremely difficult to mount. Nevertheless, many have investigated the effect of phytochemical administration in men with established prostate cancer (see Table 3). The lack of standardization in endpoints (eg. PSA, sex hormone changes) means that drawing systematic conclusions from such data is problematic, if not impossible. Other flaws in these studies include short-term administration of the phytochemical in question, highly variable sources, preparations and combinations, underpowered studies, and almost certainly inadequate dosing and scheduling of these compounds. However, the wealth of preclinical literature concerning the potential use and mechanisms of action of phytochemicals for prostate cancer will no doubt continue to provide impetus for therapeutic trials for some time to come. There are some serious pharmacological challenges in simply administering a

disease (Raffoul et al., 2007; Wang et al., 2006).

survivin production and increased apoptosis.

as well as gemcitabine in PC3 (Li et al., 2007).

may have questionable clinical effect.

**8. Conclusions** 

could find described a randomized study of the combination of soy isoflavone and curcumin compared to placebo in men who did not have prostate cancer after undergoing prostate biopsy (Ide et al., 2010); its relevance for prostate cancer can therefore be questioned.
