Prostate cancer is the most common type of cancer found in American men [37
]. Low prostate cancer incidence in Asian countries has prompted interest in dietary components in Asian diets, such as soy and tea, as cancer chemoprevention agents. When studying the combinational effects of dietary soy and green tea on hormone-induced chronic inflammation and prostate cancer, we found marked differences in responses between single food and combined dietary strategies. We demonstrated that dietary soy and green tea in combination decreased prostate inflammation and pre-cancerous lesions via attenuation of NFκB and downstream apoptotic pathways. Soy or green tea alone did not exert similar inhibitory actions, suggesting that the interactions between soy and green tea provided additional benefits against prostate cancer. Thus, the concurrent ingestion of soy and green tea may have combined activities that mitigate the risk for developing prostate cancer, particularly in the US where the consumption of these foods are limited.
There are many concerns about the in vivo
bioavailability of soy phytochemicals, but previous studies have shown that soy isoflavonoids accumulate in the prostate gland [38
]. The prostate produces active soy isoflavone metabolites and the bioavailabilities of soy isoflavones improve with long-term consumption of soy [38
]. Our results were consistent with previous observations that soy isoflavones were present at detectable levels in the plasma of soy treated rats [40
]. The soy+tea group had higher soy isoflavone concentrations than the soy group (). It is possible that green tea enhanced the absorption of soy, making soy isoflavones more bioavailable in the prostate. Plasma EGCG was not measured in the present study, but it is possible that soy constituents affected bioavailability of green tea catechins. One previous study reported that co-treatment of genistein increased uptake of EGCG in human colon cancer cells and mice [41
]. This study did not explore such mechanisms or examine the effects of other soy constituents on bioavailability of green tea catechins. Green tea may improve absorption of soy constituents by increasing activities of lactase phlorizin hydrolase (LPH) and β-glucosidase that hydrolyze isoflavone glucosides to form aglycones or glucoronidases that metabolize isoflavones for digestion and absorption. Current knowledge of the effects of green tea on β-glucosidase, LPH and glucuronidases responsible for soy metabolism is very limited. Previous studies have indicated that green tea increased hepatic UDP-glucuronosyl transferase activity in rats [42
], which might contribute to the glucuronidation of soy metabolites for more efficient transport to target tissues [5
]. Green tea may also selectively enhance growth of gut bacteria that are crucial for soy isoflavone metabolism and absorption. Studies have showed that green tea had selective bactericidal properties [44
], but no studies have investigated the effects of green tea on intestinal flora that are responsible for soy metabolism. Future work on these topics will be essential for understanding the interactions between soy and green tea in vivo
Previous findings have suggested that blocking inflammation is an effective strategy to prevent prostate cancer progression [45
]. Inhibition of the COX-2 pathway by non-steroidal anti-inflammatory drugs (NSAIDs) effectively decreased prostate tumor growth [45
], but long-term NSAIDs usage also elicited adverse gastrointestinal and vascular effects [47
]. Prostate regions susceptible to carcinoma induction also have lower expressions of anti-oxidative enzymes, including catechol-O
-methyltransferase (COMT), glutathione (GSH) and quinone reductase (QR) [49
]. When prostate cells transform to more aggressive cancerous cells, the redox balance in estrogen/testosterone metabolism shifts towards production of estradiol and activation of testosterone and DHT, leading to proliferative pressure on cells and unregulated prostatic growth [50
]. In addition, carcinogenic estrogen metabolites such as 4-hydroxyestradiol (4-OHE2
) can serve as a co-oxidants and strongly stimulate production of pro-inflammatory prostaglandins [51
]. The NFκB pathway influences many cellular responses that attribute to carcinogenesis, such as regulation of cell cycle, apoptosis and inflammation, and also intimately interacts with hormonal homeostasis. With the loss of redox balance and androgen dependency, deregulation of NFκB becomes a major promoting factor for transformation to malignancy and poor prognosis [53
]. Targeting NFκB may have important prevention or therapeutic values against prostate inflammation and cancer.
Results from the present study suggested that hormone treatments increased NFκB p50 DNA binding activities and protein expressions without affecting p65 (–). NFκB p50 has lower affinity for the IκBα regulatory element compared to p65 [54
]; therefore a selective increase in p50 subunits may lack adequate feedback mechanisms and contribute to a chronic inflammatory response. Dietary soy+tea appeared to mitigate NFκB at several levels. The combined soy+tea treatment significantly decreased protein levels of p-IκBα, NFκB p50 protein expressions and DNA binding activity. Thus, the combined treatment of soy+tea may inhibit NFκB activation via decreasing phosphorylation and subsequent degradation of its inhibitory unit, IκBα. Further examination of possible candidate upstream kinases that control IκB phosphorylation are an important area of future interest. Interestingly, soy or green tea alone did not exhibit similar protective effects as the combination treatment. Under the present conditions, neither soy nor green tea alone significantly affected inflammatory infiltration and inflammatory cytokine levels in the prostate. However, green tea decreased p50 DNA binding activity, and soy showed a trend for restoring levels of p-IκBα to that of the baseline group. Green tea also reduced hormone- induced prostate stroma enlargement, but neither soy nor green tea alone changed prostate hyperplasia outcome. Thus, soy or green tea alone might target different molecular endpoints further upstream in the NFκB pathway. Previous studies have shown that EGCG inhibits NFκB inducing kinase (NIK) and subsequent IκB-kinase (IKK)/NIK signaling complex in human lung cancer cells [21
], and genistein inhibits proteasome activity responsible for degradation of IκBα [55
]. It is possible that dietary levels of soy or green tea alone were not sufficient, but given in combination, they work targeted different pathways, and the anti-inflammatory and anti-cancer effects were amplified.
The current study shows a lack of chemopreventive effects with dietary soy or tea alone, which is in contrast to prior studies that showed high concentrations of soy isoflavone or green tea extracts induced protective effects in other models [56
]. However, similar to our findings, Cohen et al. utilized lower concentrations of soy protein isolate (≤20% by weight) in the diet and showed a lack of preventative effects against hormone refractory prostate tumor growth in rats [60
]. Previous studies utilizing green tea polyphenol extracts containing high concentrations of catechins showed efficacy in inhibiting inflammation and prostate tumorigenicity [15
], but concentrations utilized do not reflect normal human consumption. Studies looking specifically at the combined effects of soy and green tea are limited. One report indicated that genistein increased bioavailability of EGCG, but also increased intestinal tumorigenesis in APCmin/+
]. Utilizing high levels of individual bioactive agents, rather than lower levels of agents in combination, may induce adverse effects or ignore cooperative interactions among several components [62
]. Zhou et. al. reported that combination of soy phytochemical concentrate and brewed green tea synergistically inhibited prostate tumorigenicity and metastasis possibly through modulating serum testosterone and DHT in a mouse prostate cancer model [64
]. Nevertheless, they also found that green tea alone was not sufficient in inducing beneficial effects. Moreover, this study utilized a xenograft model to introduce prostate tumors, which limits the ability to examine chemoprevention at early stages of carcinogenesis. In contrast to these previous studies, the Noble rat model permitted investigation of preventative effects of dietary compounds at the early initiation and promotion stages of prostate cancer, and allowed the examination of chronic inflammation and NFκB activation. Further studies are needed to pinpoint the precise mechanism leading to the synergy between soy and green tea.
In summary, dietary soy and green tea treatments worked together, but not alone, in inhibiting inflammatory cytokine production and inducing apoptosis, possibly through NFκB-dependent pathways. Mitigation of NFκB resulted in attenuation of inflammation in the prostates and inhibited prostate carcinogenesis. Combination of soy and green tea may have provided additional beneficial effects by targeting multiple points along the NFκB pathway, and/or by targeting other mechanisms, such as improving bioavailability of active compounds in the prostate. Overall, we conclude that dietary modifications incorporating soy and green tea, which together target inflammatory and apoptotic pathways, have preventative and therapeutic values against prostate cancer development. The precise mechanism warrant further study.