**8. Conclusions**

302 Cancer Prevention – From Mechanisms to Translational Benefits

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

**6. Studies on the the combination of phytochemicals and androgen ablation**  Even though androgen suppression for metastatic disease is effective treatment, invariably, castrate resistance develops. However the recent development of new drugs that act on the androgen receptor (AR) suggest that there is still a role for androgen manipulation beyond the point traditionally defined as "castration resistance". As a result, there is renewed interest in whether phytochemicals modulate androgen receptor function in prostate cancer. It appears each phytochemical discussed in this review accomplishes androgen receptor inhibition, but all may use different mechanisms. For example, isoflavones have been shown to reduce androgen receptor transcription (Gao et al., 2004), and down regulate prostate androgen-regulated transcript-1 gene expression (Yu et al, 2003), whereas androgen receptor gene element is inhibited by lycopene in a dose-dependent manner in studies with LNCaP cells (Zhang et al., 2010). Lycopene appears to interact with AR by affecting β-catenin nuclear localization and inhibiting IGF-1 stimulated prostate cancer growth (Kucuk et al., 2002; Liu et al 2008). Resveratrol functions include the inhibition of androgen receptor transcription activity (Wang et al., 2010; Shi et al 2009) and down regulation of PSA expression (Mitchell at al, 1999; Hsieh & Wu, 2000) as tested in LNCaP cell lines. Others have shown that it also inhibits DNA binding of androgen receptor (Harada et al., 2011). Finally, androgen receptor function is inhibited by curcumin in LNCaP (Tsui et al., 2008) and in PC3 (Nakamura et al., 2002) cell lines. Curcumin appears to down regulate transactivation and expression of AR and AR-related cofactors, including activator protein-1 (AP-1), NF-kB, and cAMP response element binding protein (CREB) (Nakamura et al.,

Burich et al., (2008), showed that the combination of genistein combined polysaccharide (GCP) and bicalutamide had enhanced activity against LNCaP and LNCaPR237H cell lines. Presumably, the basis of synergistic activity observed was the ability of GCP to

In many clinical studies, the possibility that something other than the phytochemical of interest, obtained from the diet, may influence outcome has probably not been given sufficient weight in the literature. Given that foods contain many phytochemicals other than those proposed to have anti-cancer activity, it is surprising to find little work on the potential synergistic or antagonistic interactions between different phytochemicals on cancer cell lines. Further, since many experiments involve unspecified doses, sources and contents of phytochemicals, it is not possible to conclude whether true synergistic growth inhibition

Synergy or enhanced activity has been reported in prostate cancer cell lines using isoflavones in combination with paclitaxel (Ping et al., 2010), radiation (Raffoul et al., 2007), and docetaxel (Burich et al., 2008). Phenoxodiol, a novel isoflavone, in combination with

**7. Studies on the combination of phytochemicals and chemotherapy** 

downregulate AR and suppress mTOR (Tepper et al., 2007).

occurs when these agents are used in combination.

questioned.

2002).

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

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