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Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
2To whom correspondence should be addressed. E-mail: jrzhou{at}caregroup.harvard.edu
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • prostate cancer • soy phytochemicals • tea • synergy
The incidence of progressive prostate cancer is 15-fold higher in U.S. men than it is in men from Asian countries (1
–5
). Epidemiological studies suggest that the difference might be attributable to environmental factors such as lifestyle and diet, given that Asian men who adopt a Western lifestyle show increased incidence of progressive disease (6
–11
).
Very high intake of soy products is associated with reduced prevalence of aggressive prostate cancer among Asian men (5
,12
,13
). Tea polyphenols have been proposed as potential chemopreventive agents primarily because of 1) their high intake by populations with reduced cancer incidence and 2) their reported ability to inhibit proliferation and increase apoptosis in prostate cancer cells in culture (14
). In vitro and laboratory animal studies suggest that both soybeans and tea contain bioactive components that have anticarcinogenic properties, with soy isoflavones and tea polyphenols the two major groups, respectively (15
,16
).
Considerable evidence from animal studies suggests that combinations of agents can be more effective for the prevention of cancer than any single constituent (17
). Development of effective chemopreventive agents against prostate cancer in humans, however, requires conclusive evidence of their efficacy in animal models that closely emulate human disease (18
). Intraprostatic inoculation of male Severe combined immune deficient (SCID)3 mice with the human LNCaP human prostate cancer cell line represents a clinically relevant animal model of prostate cancer progression in humans (19
,20
). This orthotopic implant model incorporates androgen-regulated growth and potential for metastasis, two clinically important characteristics. It also enables use of serum prostate-specific antigen (PSA) produced by LNCaP cells as a surrogate marker of tumor growth in response to defined dietary interventions.
Earlier we showed that soy phytochemical concentrate (SPC) significantly inhibited tumor growth and metastasis to lymph nodes (20
). In the present study we evaluated combined effects of SPC and tea components on the growth and metastasis of androgen-sensitive LNCaP human prostate cancer.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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A soy phytochemical extract, SPC (Archer Daniels Midland, Decatur, IL), was used as the source of the soybean phytochemical supplement. It contained 0.52 g total soy isoflavones/g material (50.8% genistein aglycone equivalents, 40.5% daidzein aglycone equivalents and 8.7% glycitein aglycone equivalents). Glycoside forms of isoflavones represented over 95% of total isoflavones. Other phytochemicals in SPC were not quantified. All isoflavone levels were determined by HPLC by Archer Daniels Midland.
Tea infusions.
Both green tea (China Green Tea, Shanghai Tea Import and Export Corp., Shanghai, China) and black tea (Keemun Black Tea, Shanghai Tea Branch, China National Native Produce and Animal By-Products Import and Export Corp., Shanghai, China) were purchased from a local supermarket. Tea infusions were prepared by extracting tea leaves with boiling water (100°C) twice for 10 min. For animal studies, the tea infusions (15 g tea leaves/L water) were freshly prepared every Monday, Wednesday and Friday, and were used as the sole source of drinking fluid for tea-treated mice throughout the study. The catechins in tea infusions were determined by HPLC by Lipton Tea Co. (Englewood Cliffs, NJ). The compositions of a typical black tea infusion and a typical green tea infusion are shown in Table 1
.
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Both the control diet and the 5.0 g/kg SPC diet were prepared by Research Diets (New Brunswick, NJ) by using the AIN-93M formula (21
). They were used to prepare experimental diets for the following six experimental groups: 1) Control: AIN-93M; 2) SPC: AIN-93M with 5.0 g/kg SPC; 3) Black tea: AIN-93 with black tea infusion (15 g tea leaves/L water) in place of drinking water; 4) Green tea: AIN-93 with green tea infusion (15 g tea leaves/L water) in place of drinking water; 5) SPC/Black tea: AIN-93 with 5.0 g/kg SPC and with black tea infusion in place of drinking water; or 6) SPC/Green tea: AIN-93 with 5.0 g/kg SPC and with green tea infusion in place of drinking water.
Animal study.
We examined the combined effects of SPC and tea infusion on prostate cancer growth and metastasis. SPC was used because it contains most soy phytochemicals, and our previous study demonstrated that it was the potent antigrowth and antimetastasis soy component in vivo (20
). Tea infusions were used because they represent tea compositions that are typically consumed. Ninety-six 8-wk-old male SCID mice were purchased from Taconic Farms (Germantown, NY), and housed at the animal facility of Beth Israel Deaconess Medical Center in a pathogen-free environment, using laminar flow hoods and standard vinyl cages with air filters. After 1 wk of acclimation and adaptation to the AIN-93M diet, mice were randomly assigned to six groups (n = 16/group) and were subjected to one of the six experimental treatments for 2 wk. Mice were then inoculated intraprostatically with 2 x 106 LNCaP human prostate cancer cells according to previously described procedures (20
), and continued on experimental treatments for the entire experiment. Body weight and food intake were measured weekly. At 4 and 8 wk after tumor cell inoculation, phlebotomy was performed by accessing the retro-orbital venous plexus to obtain 100 µL blood from each mouse. Serum PSA level was measured by enzyme-linked immunosorbent assays (ELISA) to estimate the tumor-take rate and tumor size. The experiment was finished 10 wk after tumor cell inoculation. At the end of the experiment, the mice were killed by carbon dioxide overdose, primary tumors were excised and weighed, lymph nodes and lungs were harvested and examined for metastases and blood samples were collected. All procedures with animals were reviewed and approved by the Institutional Animal Care and Use Committee at Beth Israel Deaconess Medical Center according to NIH guidelines.
A tumor slice from each primary tumor tissue was carefully dissected and fixed in 10% buffer-neutralized formalin, paraffin-embedded and sectioned at 4 µm thickness for histology and immunohistochemistry. Lymph nodes and lungs were fixed in buffer-neutralized formalin, paraffin-embedded, sectioned and H&E stained for determinations of metastases.
Immunohistochemical determination of proliferation index.
Proliferating cell nuclear antigen (PCNA) was determined by immunohistochemical staining to determine the proliferation index, as described previously (20
,22
,23
). Both PCNA-positive proliferating cells and total tumor cells were counted in three nonnecrotic areas of each section using light microscopy at 400x magnification. The proliferation index was calculated as the percentage of PCNA-positive tumor cells relative to total tumor cells.
Immunohistochemical detection of microvessel density (MVD).
MVD was used as a marker for tumor angiogenesis and quantified by immunohistochemical staining of Factor VIII following a previously described method (20
,22
,23
). MVD was calculated by counting microvessels under a light microscope at five representative sites without necrosis of each section.
In situ detection of apoptotic index.
Apoptotic cells were determined by a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay using the ApopTag in situ Apoptosis Detection System (Oncor, Gaithersburg, MD) according to our previous procedures (20
,22
,23
). Six representative areas of each section without necrosis were selected, and both apoptotic cells and total nuclei cells were counted under a light microscope at 400x magnification. The apoptotic index was expressed as the percentage of positive apoptotic tumor cells relative to total tumor cells.
Determinations of serum levels of PSA, testosterone, and dihydrotestosterone (DHT).
The serum level of PSA was determined by ELISA, following the procedures provided by the manufacturer (Diagnostic Systems Laboratory, Webster, TX). Serum levels of testosterone and DHT were measured by enzyme immunoassay (EIA) following the procedures provided by the manufacturer (Diagnostic Systems Laboratory).
Synergy between soy and tea combination.
The nature of the combined effects of SPC and tea was determined using the method described by Yokoyama and coworkers (24
), based on the principles described by Chou and Talalay (25
). In brief, the expected value of combination effect between treatment 1 and treatment 2 is calculated as [(observed treatment 1 value)/(control value)] x [(observed treatment 2 value)/(control value)] x (control value); and the ratio is calculated as (expected value)/(observed value). A ratio of >1 indicates a synergistic effect, and a ratio of <1 indicates a less than additive effect.
Statistical analysis.
Tumor weight and measured levels of serum and tumor biomarkers were expressed as group means ± SEM. The Statview 5.0 program (SAS Institute, Cary, NC) was used to calculate two-sided comparisons among experimental groups through initial ANOVA followed by Fisher’s protected least-significant difference test (26
). Tumorigenicity rates and incidences of metastasis to lymph nodes and lungs were expressed as the percentages, and two-sided comparisons between experimental groups were tested by chi-square test or Fisher’s exact test. Values of P < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Compared with the control, the experimental treatments did not alter food intake or final body weight (Table 2
), except the final body weight of mice treated with black tea alone was increased by 16% (P < 0.05). Measurement of tea consumption indicated that mice consumed similar amounts of tea daily (data not shown).
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), which is consistent with our previous results (20
) and those of other researchers (19
). The tumorigenicity rate was lower in mice fed the experimental diet. Mice treated with SPC, black tea, green tea, the SPC/black tea combination and the SPC/green tea combination had reduced tumorigenicity rates. The tumorigenicity rates also differed between mice treated with black tea and the SPC/black tea combination, with the rate lower in the latter group (P < 0.05).
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, suggesting that the SPC/black tea combination had a synergistic inhibitory effect on tumorigenicity. On the other hand, the expected tumorigenicity rate in the SPC/green tea combination group (21.5%) was lower than the observed additive effect (35.7%) with a ratio of 0.60 (Table 3)
, suggesting the SPC/green tea combination had a less than additive effect in inhibiting tumorigenicity. Combined effects of soy phytochemicals and tea on lymph node metastases.
The SPC/black tea and SPC/green tea combinations inhibited tumor metastasis to lymph nodes. Compared with the control, dietary SPC or tea treatment alone did not reduce the incidence of tumor metastasis to lymph nodes (Table 3)
. However, mice treated with the SPC/black tea or SPC/green tea combination had a lower incidence of lymph node metastases (Table 3)
. The incidences of lymph node metastasis in both combination groups were less than the expected values, with ratios of 2.13 and 1.87, respectively, suggesting that both the SPC/black tea and SPC/green tea combinations synergistically inhibited prostate tumor metastasis to lymph nodes.
Combined effects of soy phytochemicals and tea on final tumor weight and serum PSA levels.
Compared with the control (Fig. 1A
), all treatments other than green tea alone significantly reduced the final tumor weight. However, green tea alone tended to reduce final tumor weight (22%, P = 0.11). The combined effects of the SPC/black tea combination (93%) and the SPC/green tea combination (88%) on final tumor weight reduction were greater than the expected additive effects (91 and 70%, respectively), suggesting that the combination of SPC with either black tea or green tea synergistically inhibited final tumor weight. In parallel, serum levels of PSA, a marker that is secreted by LNCaP cells and reflects tumor size, in mice in the experimental groups other than the green tea group were reduced (Fig. 1
B), compared with the control. Comparisons of expected and observed values suggest that SPC combined with black tea or green tea synergistically reduced serum PSA concentration.
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Compared with the control (Fig. 2A
), proliferation indices of primary tumors in all experimental groups were significantly reduced by 44–75%. Although the SPC/black tea combination and SPC/green tea combinations tended to further reduce tumor cell proliferation (P = 0.001 and P = 0.002, respectively, compared to the control), no apparent synergistic effects were observed.
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B). No apparent synergistic effects between SPC and tea on tumor angiogenesis were observed. The treatments did not affect the tumor cell apoptotic index (data not shown). Combined effects of soy phytochemicals and tea on serum testosterone and DHT concentrations.
Mice treated with black tea tended to have a greater serum testosterone concentration (34.4%, P = 0.50) and had a 72% lower DHT concentration than controls (P < 0.05), suggesting that black tea may contain components that inhibit the activity of 5
-reductase, an enzyme that converts testosterone to the more bioactive DHT. Green tea tended to increase serum testosterone and DHT levels by 73.8% (P = 0.14) and 194% (P = 0.076), respectively. The combination of SPC and green tea reduced serum levels of DHT (P < 0.05).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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and Fig. 1
). To our knowledge, this is the first in vivo study to demonstrate that two major components of the Asian diet can synergistically prevent prostate cancer.
Several in vitro and in vivo studies have shown that green and black tea polyphenols have chemopreventive effects on prostate carcinogenesis (16
,18
,27
). Studies of tea polyphenols suggest that epigallocatechin gallate (EGCG) is the major bioactive component in green tea and less is present in black tea. Black tea also contains other tea polyphenols such as theaflavins and thearubigins (28
). Multiple studies also suggest that components in dietary soy have anticarcinogenic effects on prostate tumors. The chemopreventive properties of the soy isoflavone genistein have been the subject of extensive in vitro (23
,29
,30
) and in vivo (20
,23
,31
–33
) research. We have also shown that soy phytochemicals other than genistein, in particular, SPC, inhibit prostate cancer progression and tumor metastasis in vivo (20
).
Several lines of evidence show that angiogenesis is essential for the growth and metastases of solid tumors (34
). Our results indicate that soy bioactive and tea components slow progression of LNCaP human prostate tumors, partly by inhibiting formation of new blood vessels (Fig. 2
B). However, we did not find a significant correlation between this marker of end point tumor angiogenesis and markers for prostate cancer progression (e.g., tumor weight and serum PSA). It has been proposed that angiogenesis balance may play a critical role early in the process of tumor progression (35
). It is possible that soy or tea bioactive components play more important roles in the early stages of tumor progression by modulating angiogenic/antiangiogenic factors. Further study of this modulation in vivo is expected to facilitate our understanding of the mechanisms by which soy and tea bioactive components may synergistically inhibit the progression of prostate tumors.
Androgen is a prerequisite for the development of benign prostatic hyperplasia and prostate cancer. In the prostate, testosterone is rapidly and irreversibly converted to a more biologically active metabolite, DHT, by catalysis of 5-reductase. EGCG has been shown to inhibit the growth of prostate cancer cells in vitro (36
) and in vivo (37
) through mechanisms that might involve inhibition of type I 5-reductase (37
). In this study, black tea reduced serum levels of DHT (Fig. 2
D), suggesting that black tea may have bioactive components that inhibit the conversion of testosterone to DHT, presumably via inhibition of 5-reductase in this SCID-LNCaP animal model. It is unclear whether black tea theaflavins, EGCG and/or other components are responsible for this function in vivo.
On the other hand, green tea did not reduce the serum level of DHT, but instead tended to increase it (P = 0.076) (Fig. 2
D), and we found that green tea treatment did not inhibit tumor growth (Fig. 1
A). Green tea contained more EGCG than black tea (Table 1)
, and studies have shown that EGCG inhibits the activity of 5-reductase (38
). These results derived from our animal model suggest that, although EGCG may be a potent antitumor agent in green tea and inhibit 5-reducatase activity, green tea contains other constituents that may counteract EGCG’s antitumor activity, in part by counteracting its modulation of 5-reducatase activity. Further research is required to identify these constituents and study their effects and/or their interactions with other components on prostate cancer. Our results demonstrate the importance of evaluating the benefit of whole tea products, rather than just isolated tea catechins or EGCG, on prostate cancer prevention because other tea constituents may play important roles.
Green tea combined with SPC reduced total testosterone and DHT levels (Fig. 2
A, B), suggesting that interactive modulation of androgen levels is one of the important mechanisms for the synergistic prevention of prostate cancer progression by the soy/green tea combination. This study supports the use of appropriate combinations of bioactive dietary agents, such as soy and tea, as effective nutritional regimens for prostate cancer prevention and treatment.
In summary, both black tea and green tea inhibited tumorigenicity rates of LNCaP tumors. Although tea contains bioactive catechins, it contains other components that contribute to its anticancer activity. Black tea inhibited prostate cancer tumorigenicity, metastasis and final tumor weight in association with a reduced serum level of DHT. Green tea did not reduce final tumor weight in association with a tendency to increase serum androgen levels.
The combination of soy phytochemicals and tea synergistically inhibited tumorigenicity, final tumor weight and metastasis to lymph nodes in vivo. In particular, the synergistic inhibition by the green tea and SPC combination on tumor progression and metastasis is associated with effective reductions of serum levels of both testosterone and DHT. This study supports further investigations using soy and tea combinations as effective nutritional regimens for prevention of prostate cancer. It shows for the first time that the Asian diet effectively prevents prostate cancer progression in part via synergistic interactions of bioactive components.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DHT, dihydrotestosterone; EIA, enzyme immunoassay; EGCG, epigallocatechin gallate; ELISA, enzyme-linked immunosorbent assay; MVD, microvessel density; PCNA, proliferating cell nuclear antigen; PSA, prostate-specific antigen; SCID, Severe combined immune deficient; SPC, soy phytochemical concentrate; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling.
Manuscript received 29 July 2002. Initial review completed 17 September 2002. Revision accepted 23 October 2002.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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