**3. Promising anti-inflammatory natural products in PCa**

The role of inflammation in prostate cancer etiology stems from studies accessing the rela‐ tionship between intake of anti-inflammatory dietary compounds and prostate cancer risk. Epidemiological evidence associates or significantly correlates consumption of tomato [73], soy and green tea [74, 75] with decreased prostate cancer risk. Furthermore, animal studies confirm that the anti-inflammatory properties of both soy and green tea cause a decrease in prostate cancer [74, 75]. One study involving Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice fed a diet enriched with processed whole tomatoes reported benefits including increased survival, delayed progression from PIN to PCa cancer and a decreased incidence of poorly differentiated PCa cancer [76]. Prostate cancer cell lines treated with phytoestrogens, specifically genistein and daidzein, indicate a decrease in prostate cancer risk, however this effect seems to be linked to epigenetic modifications of DNA [77].

#### **3.1. PUFA and prostate cancer**

Interest in dietary fats and disease etiologies has emerged because of their known antiinflammatory properties. Examples of dietary fat which are essential in a variety of mammalian biological processes and impact PCa include omega-3 (n-3) and omega-6 (n-6) PUFA [78, 79]. In published cell line and xenograft studies, n-6 PUFA (linoleic acid and arachidonic acid) typically exert a growth-promoting effect, while n-3 PUFA (EPA and DHA) have growthinhibitory effects [80-85]. *In vitro* and animal studies suggest a trend of opposite effects for cancer development with respect to n-3 and n-6 PUFA. The n-3 PUFA, such as EPA and DHA, indicate a suppression of tumor carcinogenesis, however n-6 PUFA seems to promote tumor development. From an epidemiological perspective, evidence of an association between particular PUFA and PCa is inconsistent, with many studies reporting no association between dietary intake of n-3 or n-6 PUFA and the risk of PCa [86-92], however both pre-clinical *in vivo* and *in vitro* studies clearly indicate that there are biological mechanisms by which omega-3 PUFA can arrest growth in both PCa cells and tumors. Supplementation of n-3 PUFA in animal studies failed to produce an effect on prostate tumor growth or other markers of PCa progres‐ sion and did not significantly reduce tumor growth in a PCa mouse model [93-96]. Treatment of human PCa cells with n-3 PUFA has been shown to consistently inhibit proliferation and /or increase programmed cell death, affect gene expression and deter properties of invasive human PCa in cells supporting the notion that EPA and DHA supplementation could preclude or limit the growth of prostate tumors [80, 85, 94, 97-102]. In general, and as found in a recent case-control study, while proinflammatory n-6 PUFA may present an increase in PCa risk, the anti-inflammatory properties of n-3 PUFA have been noted in their association with decreased risk [103]. Interestingly, this same study reported that mutations in the inflammation and mitogenesis related gene (COX-2), combined with low nutritional consumption of n-3 PUFA, had a higher risk of PCa; this risk was lowered with an increase in the dietary intake of n-3 PUFA [103]. Inflammatory gene expression is usually negatively associated with cancer stage and prognosis [104]. Despite these trends, a recent epidemiology study by Brasky (2011) contradicts the protective role of n-3 PUFA in PCa by reporting a positive association with DHA for high-grade disease[40]. Specifically the findings indicate that higher blood concen‐ trations of n-3 PUFA are associated with increased risk of high-grade prostate cancer (Gleason score 8–10), and higher concentrations of n-6 PUFA were associated with decreased risk [40]. Dr. Brasky has indicated that these findings *"turn what we know—or rather what we think we know—about diet, inflammation and the development of prostate cancer on its head and shine a light on the complexity of studying the association between nutrition and the risk of various chronic diseases* [105]." Could it be that what is deemed good and promoted for heart and brain health may be essentially harmful to the prostate? Consider the following: Data analyzed to come to this vastly different conclusion was based on a subset of more than 3200 (half of which developed PCa throughout the duration of the study) from the overall study population of 19,000 [40]. This nationwide randomized clinical trial was initiated to test the efficacy of the drug finasteride to prevent prostate cancer and considered unique as biopsy was used to confirm the absence or presence of prostate cancer in all study subjects [105]. The original intent of the study was to prove the hypothesis that n-3 PUFA would reduce and n-6 PUFA and transfatty acids would increase prostate cancer risk, pre-empted by two important known factors; that n-3 fatty acids originating mainly in fish and their oil supplements have anti-inflammatory properties and chronic inflammation is known to increase the risk of several cancers. All this combined with an inconsistent history of studies and the fact that the mechanisms behind the influence of n- 3 PUFA on the risk of developing high-grade PCa have not been identified, warrants further research. Nonetheless, we are presented with evidence of substantive biological activity, and thus we must explore other mechanisms, aside from inflammation, that may play a greater role in the development of certain prostate cancers. To embark upon this currently debatable journey, there are key factors concerning prostate cancer and dietary interventions that should be considered, particularly n-3 PUFA. The sections to follow are meant to generate, by example and based on the current literature, some thoughts on how to proceed in this area of research to determine the actual role of n-3 PUFA in prostate cancer.
