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Clinical Cancer Research Vol. 6, 230-236, January 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

The Potential of Soybean Foods as a Chemoprevention Approach for Human Urinary Tract Cancer1

Shu-Jem Su, Trai-Ming Yeh, Huan-Yao Lei and Nan-Haw Chow2

Departments of Microbiology and Immunology [S-J. S., T-M. Y., H-Y. L.], Medical Technology [T-M. Y.], and Pathology [N-H. C.], College of Medicine, National Cheng Kung University, Tainan, Taiwan 70101, Republic of China


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Isoflavones are excreted in human urine and can be modulated by soy-rich diets. Recently, isoflavones were suggested to have protective effects against bladder cancer cells. We sought to determine the efficacy of the antitumorigenic effects of isoflavones at concentrations found in the range of human urine excretion and compare normal urothelium and bladder cancer cells for differential cytotoxicity. A total of seven human bladder cancer cell lines and an immortalized uroepithelial cell line were used to examine the effects of genistein, daidzein, and biochanin-A, either individually or as an equal-proportion mixture regimen, on cell growth, DNA synthesis, alterations of cell cycle distribution, and induction of apoptosis. The role of cyclin B1 and cdc2 kinase in cell cycle arrest was analyzed. In addition, severe combined immunodeficient mice were used to confirm the anticancer effects of isoflavones in vivo. Cooperative action of isoflavones was more effective in growth inhibition and apoptosis induction than any single compound. Genistein tends to cause a dose-dependent induction of G2-M cell cycle arrest and an inhibition of cdc2 kinase activity. However, both daidzein and biochanin-A directly induced apoptosis without altering cell cycle distribution. The IC50 values in non-transformed cells were higher than those in most cancer cell lines, and the IC50 of the mixture regimen was within reach of the levels observed in urine after a soy challenge. Furthermore, both genistein and combined isoflavones exhibited a significant tumor suppressor effect in vivo (P < 0.05). The results justify the potential use of soybean foods as a practical chemoprevention approach for patients with urinary tract cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Transitional cell carcinoma is the most important cancer of the urinary tract and occurs in the renal pelvis, ureter, urinary bladder, and urethra. The incidence of this cancer and the number of deaths from this cancer are generally increasing, notably in economically developed societies. It is well known that field cancerization is an important characteristic of tran-sitional cell carcinoma and may affect the natural course of disease progression. For example, enhanced expression of tumor-associated antigens could be shown in normal-appearing urothelium (1, 2, 3) , and the degree of epithelial dysplasia predicts the risk of disease progression (4) . As a result, it is imperative to modulate carcinogenesis as early as from the initiated cells in the field mucosa.

A number of epidemiological studies have reported that increased soy consumption is associated with a reduced risk of breast, colon, and prostate cancer for peoples living in Asia as compared with peoples living in America and Western Europe (5) . Further support for the potential of isoflavones as natural chemopreventives is the dose-dependent response of urinary isoflavone excretion to soy consumption from low to higher doses (6 , 7) . Animal studies also found that soybean feeding has a protective effect on bladder carcinogenesis in Swiss albino mice (8) and on a transplantable murine tumor (9) . A recent report showed that genistein (5,7,4'-trihydroxyisoflavone), daidzein (7,4'-dihydroxyisoflavone), biochanin-A, and phytochemical concentrate tend to cause a dose-dependent inhibition of proliferation in J82 human cancer cells (9) . A G2-M-phase cell cycle arrest could be demonstrated in both the J82 and UM-UC-3 cell lines. Because isoflavones are excreted in human urine, and the levels are positively associated with the frequency of soy intake (10) , this group of compounds deserves investigation in the context of dietary chemopreventives for urinary tract cancer. This study was performed to address the following questions: (a) do the cancer protective effects apply to bladder cancer of various histological grades? (b) is there any toxicity to normal urothelium if isoflavones are used as treatment? and (c) what is the biological efficacy of mixed soy isoflavones at concentrations found in the range of human urine excretion?


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell Culture and in Vitro Growth Evaluation and Reversibility of Growth Inhibition.
The human bladder cancer cell lines RT4, J82, HT1376, and T24 were obtained from the American Type Culture Collection (Manassas, VA). Both TSGH8301 and BFTC905 were established locally and have been reported in detail previously (11 , 12) . The E6 cell line was an immortalized human uroepithelium (13) .

To examine the efficacy of growth inhibition induced by isoflavones, genistein (Life Technologies, Inc.), daidzein (Calbiochem-Novabiochem), and biochanin-A (Sigma) were dissolved in DMSO (Sigma) for in vitro study and animal experiments. The cell number was counted using the crystal violet elution method (14) .

[3H]Thymidine Incorporation.
To evaluate the rate of DNA synthesis, cells (1 x 103) that had been treated with isoflavones and [3H]thymidine (0.2 mCi/well) for 18 h were counted.

DNA Fragmentation Analysis.
The DNA fragmentation study was basically performed as described previously (15) . Briefly, cells were lysed with lysis buffer [20 mM Tris (pH 8.6), 1 mM EDTA, and 0.4% Triton X-100], and the supernatants were collected by centrifugation at 10,000 x g for 10 min. After precipitation, DNA samples were separated by 1% or 1.5% agarose gel electrophoresis and visualized by ethidium bromide staining.

Cell Cycle Analysis and Measurement of Apoptosis.
The cell cycle distribution was estimated by flow cytometric DNA analysis according to standard procedures (15) . Briefly, 1 x 106 cells were cultured and treated with or without different concentrations of isoflavones. These cells were then stained with fluorochrome DNA staining solution and analyzed using a FACSsort cytometer (Becton Dickinson, San Jose, CA). The percentage of cells in different cell cycle phases (G0-G1, S phase, and G2-M phase) was calculated using Lysis II Software. The sub-G0-G1 peaks were considered apoptosis.

Cyclin B Protein Estimation.
The amount of cyclin B protein was estimated as described previously (16) . Cell extracts were prepared by the addition of SDS loading buffer [50 mM Tris-HCl (pH 6.8), 2% SDS, 10% glycerol, and 100 mM DTT], 1 mM phenylmethylsulfonyl fluoride, and 1x mixture of protease inhibitors (Sigma) for 10 min. After boiling, the extracts were put on ice and centrifuged (12,000 rpm, 4°C) for 20 min. The protein sample (500 µg) was resolved by 12% SDS-PAGE, blotted to nitrocellulose paper, and immunoblotted with antihuman cyclin B1 monoclonal antibody (Santa Cruz Biotechnology). The immune complexes were visualized using an enhanced chemiluminescence detection system (Amersham Life Science).

cdc2 Kinase Assay.
cdc2 kinase activity was estimated according to the procedure described previously (17 , 18) . Protein quantitation was performed using the BCA assay (Pierce, IL). Each cell line (100 µg) was incubated with anti-cdc2 kinase monoclonal antibody (2 µg; Santa Cruz Biotechnology), followed by a protein A-Sepharose reaction on a rotator. The resulting immune complexes were assayed for kinase activity in reaction buffer containing 2.4 µg of histone H1, 10 Ci/mmol of [{gamma}-32P]ATP, and 0.3% DMSO or genistein (5, 10, and 20 µg/ml). Then reaction was stopped and resolved by 12% SDS-PAGE. The phosphorylated H1 proteins were visualized by autoradiography.

SCID3 Mice Xenograft Model.
TSGH8301 cells (1 x 107) were injected s.c. into the backs of 6-week-old male mice, as described previously (19) . Engrafted tumors were then treated with 0.025% DMSO, 50 µg of genistein, or a mixture regimen (20 µg of genistein, daidzein, and biochanin-A) every 3 days (n = 6 for each group). The largest diameter of the tumor was measured, and tumor volumes were calculated.

Statistical Analysis.
Unpaired Student’s t test (two- sided) was used to determine the differences in IC50 values and cell cycle distribution among the cell lines tested, and mean tumor size of mice in different study groups was analyzed by Statworks (Cricket Software, Inc.). The levels of significance were set at P < 0.05.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effect of Isoflavones on the Cell Growth of Human Bladder Cancer.
The effects of genistein, daidzein, and biochanin-A were tested on bladder cancer cell lines individually at various concentrations or as a mixture regimen. A dose-dependent inhibition of cell growth by each isoflavone was observed in all cell lines tested (Fig. 1)Citation . Although the sensitivity of each cell line varied, genistein was the most potent growth inhibitor, followed by biochanin-A and then daidzein. The mixture regimen had a greater inhibitory effect than any single compound. As summarized in Table 1Citation , there was a trend toward positive correlation between IC50 for genistein and histological grading of cancer cells. Except for HT1376 cells, the IC50 value was higher in E6 control cells than in most cancer cell lines (P < 0.05, respectively).



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  		Fig. 1. The inhibition of isoflavones on cell growth. Different concentrations of isoflavones were incubated with cancer cells (1 x 104) for 3 days. After treatment, cell numbers were counted in triplicate and expressed as a percentage (mean ± SD) compared with controls. G+B+D, genistein + biochanin-A + daidzein.

 

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  		Table 1 The IC50 of isoflavones (µg/ml) in human uroepithelial cell lines

 
The reversibility test showed that the ability to recover from isoflavone inhibition was inversely related to the dosage, i.e., the higher the doses of isoflavone, the less chance of recovery from inhibition (data not shown). The results suggest that isoflavones are cytostatic at dosages lower than the IC50 but become cytotoxic at higher dosages. Each cell line had its own cutoff value for irreversible inhibition. The values for the J82 cell line, for example, were 20 µg/ml genistein, 30 µg/ml biochanin-A, and 50 µg/ml daidzein, respectively (Fig. 2)Citation . The thymidine incorporation study found a dose-dependent inhibition of DNA synthesis by isoflavones in all cell lines in the range of 10–50 µg/ml (data not shown).



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  		Fig. 2. Reversibility of growth inhibition by isoflavones. J82 cells (5 x 103) were treated with appropriate concentrations of isoflavones dissolved in DMSO (less than 0.5% v/v) for 3 days, and cell counts were measured after incubation with DMEM for 2 days. The values were expressed as the means of three experiments. DMSO was used as control. G, genistein; BA, biochanin-A; D, daidzein.

 
Apoptosis Induction by Isoflavones.
DNA fragmentation was used to test the occurrence of apoptosis after isoflavone treatment. Variable degrees of DNA ladder could be verified in most cancer cell lines, supporting the apoptosis-inducing ability of isoflavones. Typical results from TSGH8301, BFTC905, and T24 cells are shown in Fig. 3Citation .



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  		Fig. 3. DNA fragmentation induced by isoflavones. Exponentially growing cells were treated with isoflavones for 48–72 h. DNA samples were electrophoresed by 1% or 1.5% agarose gel. a, TSGH8301; b, BFTC905; c, T24. Lane M, molecular weight markers; Lane C, DMSO-treated cells; Lane G50, genistein (50 µg/ml); Lane B-A50, biochanin-A (50 µg/ml); Lane D50, daidzein (50 µg/ml).

 
Effect of Isoflavones on Cell Cycle Progression.
Flow cytometric analysis showed that there was no apparent cell cycle arrest if isoflavones were lower than 5 µg/ml (data not shown). High-grade cancer cells (TSGH8301, T24, and J82) were found to have a significant dose-dependent reduction of G1 phase together with an increased G2-M phase when genistein reached concentrations of 10 or 20 µg/ml (P < 0.05, respectively). However, there was no alteration of cell cycle distribution in the E6 and RT4 cell lines (Table 2)Citation . Representative results from J82 cells are shown in Fig. 4Citation . The apoptosis induction by genistein appears to be dose dependent and kinetic dependent, but biochanin-A and daidzein induced apoptosis without any alterations in cell cycle distribution (Fig. 4)Citation .


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  		Table 2 Distribution of cell cycle phase in response to genistein treatment in vitro

 


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  		Fig. 4. Effects of isoflavones on cell cycle progression and apoptosis induction. J82 cells (1 x 106) were grown in the absence or presence of isoflavones at 10 µg/ml or 50 µg/ml for 24 and 48 h, respectively. The cell cycle distribution was analyzed by flow cytometry.

 
Biochemical Target of Cell Cycle Arrest Induced by Genistein.
To elucidate the mechanism through which genistein induces G2-M cell cycle arrest, both cdc2 kinase activity and cyclin B1 protein expression were evaluated in each cell line. There was no apparent difference in cyclin B1 expression in relation to genistein treatment (Fig. 5)Citation . However, a dose-dependent inhibition of the cdc2 kinase activity, corresponding to the observed cell cycle arrest effect, was observed in most bladder cancer cell lines, except E6 and RT4 (Fig. 6)Citation .



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  		Fig. 5. Effect of genistein on cyclin B1 expression. Human bladder cancer cells were treated with genistein of 10 (G10), or 20 (G20) µg/ml for 24 h. Representative results of cyclin B1 expression from TSGH8301, T24, and J82 cells are shown.

 


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  		Fig. 6. Effect of genistein on cdc2 kinase activity. Human bladder cancer cell extracts were treated with or without genistein of 5 (G5), 10 (G10), or 20 (G20) µg/ml. Representative results from E6, RT4, TSGH8301, T24, and J82 cell lines are shown.

 
The Anticancer Effects of Isoflavones in Vivo.
To verify the anticancer effects of isoflavones in vivo, engrafted TSGH8301 cells in SCID mice were treated with genistein or the mixture regimen. The 50–70-fold increase in tumor size observed over a 2–3-week period in animals treated with DMSO was significantly decreased when genistein or the isoflavone combination was injected s.c. (P < 0.05, respectively; Fig. 7Citation ). However, there was no apparent difference between the mice treated with genistein and those treated with the combination regimen (P > 0.1). Moreover, no significant cancer protection was noticed when isoflavones at the same dosages were injected directly into the i.p. cavity (data not shown). No metastasis was seen in any mouse during the study period (data not shown).



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  		Fig. 7. Effects of genistein or combined isoflavones on the growth of TSGH8301 cells in SCID mice. Tumor cells (1 x 107) were injected s.c. into SCID mice. Experiments began when the appropriate nodule size was reached. DMSO or isoflavones were given every 3 days and compared for their anticancer potency. DMSO (0.025%) was used as a control.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Recent advances in molecular biology demonstrate that a loss of genetic material on multiple chromosomal loci is required for transformation of normal epithelium to frank cancer (20) . Mucosa field changes and their prognostic significance support that early transformed cells are present in the urothelium of patients with transitional cell carcinoma. Because continued exposure to carcinogenic stimuli may induce additional genetic alterations that lead to tumor recurrence/progression, systemic therapy to the field mucosa may be the most practical way to halt or reverse the carcinogenic process.

In this study, we demonstrate that genistein induces a dose-dependent G2-M-phase cell cycle arrest; but both daidzein and biochanin-A directly induce apoptosis without altering cell cycle distribution. In addition, the cooperative action of isoflavones is more effective in the inhibition of cell growth, DNA synthesis, and apoptosis induction than any single compound. Our data thus support that part of the antitumorigenic effects of isoflavones may be derived from G2-M-phse cell cycle arrest and/or apoptosis induction. Further support for the clinical relevance of isoflavones comes from the differential cytostatic/cytotoxic effects between E6 and most cancer cell lines. Actually, the IC50 values of the mixture regimen (3–5 µg/ml or 7.9–13.2 µM) in most cancer cell lines are within reach of the urine levels of daidzein (14.7 µM) and genistein (8.4 µM) after a soy challenge (12) , confirming the potential of soybean foods in prevention of urinary cancer.

Several biochemical targets have been proposed to explain the cancer-preventive effect of isoflavones (21) . For example, genistein is a specific inhibitor of tyrosine kinases, DNA topoisomerases I and II, and ribosomal S6 kinase. Furthermore, high concentrations of isoflavones could inhibit angiogenesis and scavenge DNA reactive agents (22) . We provide evidence that down-regulation of cdc2 kinase activity is one of the molecular mechanisms responsible for the cell cycle arrest induced by genistein. Nevertheless, daidzein and biochanin-A were found to induce apoptosis without alterating cell cycle progression, suggesting that multiple mechanisms may be responsible for the anticancer effects of isoflavones.

The purpose of chemoprevention is to defer the progression of disease. If the occurrence of cancer is deferred for one or more decades (for example, from age 60 years to 80 years), then the "prevention" is very substantial and worthwhile. The current study suggests that isoflavone excretion in human urine could inhibit or retard the progression of bladder carcinogenesis. The hypothesis, if verified by randomized, controlled trials, may be of great clinical impact. Because urinary isoflavones are increased only on the first day after challenge and will recover to prechallenge levels on the second or third day (12) , regular soy-based diets could be recommended as a chemoprevention approach for patients with urinary tract cancer or for those individuals with high-risk occupations. Taken together with the fact that diets high in vegetables and fruits are the most effective means of preventing bladder cancer (23 , 24) , dietary change can be considered a practical strategy in confronting urinary tract cancer.


   ACKNOWLEDGMENTS
 
We thank Lien-Ping Kao and Wei-Ber Liu for technical assistance and Prof. Min-Der Lai for his kindness in providing some of the bladder cancer cell lines used in this study.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Grants NSC88-2314-B-006-051 and NSC88-2314-B-006-079 from the National Science Council, Taiwan, Republic of China and Grant NCKUH-88-037 from the National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan, Taiwan 70428, Republic of China. Phone: 886-6-2741928; Fax: 886-6-2383678; E-mail: chownh{at}mail.ncku.edu.tw Back

3 The abbreviation used is: SCID, severe combined immunodeficient. Back

Received 6/14/99; revised 10/ 4/99; accepted 10/ 6/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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H.-L. Cheng, B. Trink, T.-S. Tzai, H.-S. Liu, S.-H. Chan, C.-L. Ho, D. Sidransky, and N.-H. Chow
Overexpression of c-met as a Prognostic Indicator for Transitional Cell Carcinoma of the Urinary Bladder: A Comparison With p53 Nuclear Accumulation
J. Clin. Oncol., March 15, 2002; 20(6): 1544 - 1550.
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