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

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 occurs when these agents are used in combination.

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

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 survivin production and increased apoptosis.

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

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 may have questionable clinical effect.
