**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., 2002).

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