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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:287-290, February 2005

Nutrition and Cancer

Lycopene Inhibits the Growth of Human Androgen-Independent Prostate Cancer Cells In Vitro and in BALB/c Nude Mice1

Lili Tang, Taiyi Jin*, Xiangbin Zeng{dagger} and Jia-Sheng Wang2

Department of Environmental Toxicology and The Institute of Environmental and Human Health, Texas Tech University System, Lubbock, TX; * Fudan University, Shanghai, China; and {dagger} Tulane University School of Medicine, New Orleans, LA

2To whom correspondence should be addressed. E-mail: js.wang{at}ttu.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Lycopene is a promising chemopreventive agent for human prostate cancer. To test the hypothesis that the effect of lycopene on prostate cancer is stage specific in the process of carcinogenesis, inhibitory effects of natural lycopene on the proliferation of 3 different human prostate carcinoma cell lines were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Lycopene more potently inhibited the growth of the androgen-independent DU145 and PC-3 cells than androgen-dependent LNCaP cells. The 50% inhibitory concentration of lycopene for these cell lines was 26.6 µmol/L for DU145, 40.3 µmol/L for PC-3, and 168.5 µmol/L for LNCaP. We also studied the inhibitory effect of lycopene on the growth rate of DU145 tumor xenografts in BALB/c male nude mice. The tumor growth rate was inhibited by 55.6 and 75.8% in mice treated with 100 and 300 mg/kg lycopene, respectively, compared with controls. In addition, no tumors formed in 1 mo in mice treated with DU145 cells that had been pretreated with 20 µmol/L lycopene; however, they did form when DU145 cells were not pretreated. Flow cytometry revealed that lycopene caused DU145 cells to accumulate in the G0/G1 phase and to undergo apoptosis in a dose-dependent manner. The rate of apoptosis was up to 42.4% lower in DU145 cells treated with 32 µmol/L lycopene compared with the untreated control cells. These results suggest that lycopene may specifically inhibit the growth of androgen-independent prostate cancers.

KEY WORDS: • lycopene • prostate cancer cells • chemoprevention

Prostate cancer is the most common visceral malignancy in American men, accounting for 33% of all male cancer incidences and 10% of all male cancer mortality in the United States. The American Cancer Society estimated that there were 230,110 new prostate cancer cases and 29,500 prostate cancer deaths in 2004 (1). The etiology of prostate cancer is not clear; currently accepted risk factors for prostate cancer include age, race, dietary habits, and androgen levels (2). Dietary and nutritional factors are considered important modulating factors in the development of prostate cancer (3,4). Positive associations were documented for dietary fats and total energy intake, whereas negative associations were found for intakes of vitamins, carotenoids, and phytoestrogens (5–7).

Chemoprevention was proposed to be an effective approach to reduce the incidence of many types of cancers, including prostate cancer (3). The majority of human epidemiologic studies showed an inverse association between dietary intake of tomatoes and tomato products, and prostate cancer risk (2–9). Lycopene, a 40-carbon acyclic carotenoid with 11 linearly arranged conjugated double bonds, is present in high amounts in tomatoes and tomato-derived products (10). It is the most efficient single oxygen quencher among carotenoids and has potent antioxidant properties (11). Results from short-term clinical intervention studies demonstrated a very promising protective effect of lycopene against prostate cancer (12,13). Under experimental conditions, lycopene inhibited the growth of a variety of cancer cells, including prostate cancer cells (14,15), although data from whole animal models were not entirely consistent (16–18).

We hypothesized that the inhibitory effect of lycopene on the process of prostate cancer formation is stage specific. As part of our efforts to test this hypothesis, we studied the inhibitory effects of natural lycopene (isolated from tomato with purity > 95%) on the proliferation of the well-characterized human prostate carcinoma cell lines (the androgen-independent DU145 and PC-3 and the androgen-dependent LNCaP). Because lycopene more potently inhibited the growth of the androgen-independent cells than the androgen-dependent cells, we conducted a series of antitumorigenic experiments in DU145 cells to test the hypothesis that natural lycopene specifically inhibited prostate cancer growth through an androgen-independent mechanism.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Materials. Natural lycopene (>95% pure) and 6% lycopene oleoresin extracted and purified from tomatoes according to a previously published method (19) were kindly provided by Prof. Xiaoling Ding at the Southern Yangtze University, Wuxi, China. The purity was verified by HPLC with UV detection at 470 nm using an authentic lycopene standard obtained from Sigma. Lycopene was stored at –80°C, and 10 mmol/L stock solutions were freshly prepared with tetrahydrofuran (THF, Sigma) before the start of the experiments. Human prostate carcinoma cell lines, the androgen-independent DU145 and PC-3 cells and the androgen-dependent LNCaP cells, were obtained from American Type Culture Collection. Cell culture supplies and media components were purchased from Gibco. Other chemicals and reagents were purchased commercially at the highest degree of purity available.

    Cell culture and viability assay. DU145, PC-3, and LNCaP human prostate cancer cells were cultured in DMEM/Ham’s F12 medium (Gibco) containing 10% fetal bovine serum, 2 mmol/L L-glutamine, 100 kU penicillin/L and 100 µg/L streptomycin. The cells were incubated at 37°C in a 95% air, 5% CO2 atmosphere until they approached ~80% confluence. To evaluate the effect of lycopene on the viability of DU145, PC-3, and LNCaP cells, 5 x 103 cells in 100 µL of medium were added to a flat-bottomed 96-well plate. After 24 h of cultivation, the medium was changed to fresh medium supplemented with lycopene or THF alone. Unless otherwise stated, the lycopene-containing media were replaced daily. Cell viability was evaluated by microtitration assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (20) after designated times of cultivation. The results were expressed as the percentage of the control culture treated with vehicle alone (THF).

    Analysis of cell cycle distribution and rate of apoptosis. The androgen-independent DU145 cells were grown in 25-cm2 flasks and treated with various concentrations of lycopene for 48 h. The cells were digested by trypsin-EDTA, washed, and resuspended in serum-free medium, counted, and then fixed in 75% ethanol at 4°C. The fixed cells were then washed and resuspended in PBS (pH 7.4), treated with RNase, stained by propidium iodide, and incubated at 37°C for 30 min. Stained cells were analyzed by FACScalibur (Becton Dickinson) for DNA fragmentation and cell cycle stage using the program provided by the manufacturer.

    Nude mouse tumor assay. The study was approved by the Animal Use and Care Committee of The Institute of Environmental and Human Health, Texas Tech University. Male BALB/c nude mice were purchased at 4–6 wk of age from Harlan. Mice were housed in laminar airflow cabinets under pathogen-free conditions with a 12-h light:dark schedule and fed autoclaved semipurified diet (AIN-93) and water (21). DU145 cells at 70–80% confluence were washed with PBS, harvested with trypsin/EDTA, and resuspended in F-12 medium at a concentration of 1 x 107 cells/100 µL Matrigel matrix (Becton Dickinson). Male athymic mice were injected s.c. with 100 µL of the cell/Matrigel matrix on the dorsal surface. After 24 h, mice were gavaged with different doses of lycopene (0, 10, 100, and 300 mg/kg body weight) for 8 consecutive weeks at the rate of 5 d/wk. Once each week, mice were weighed, and tumor volume was measured using the following formula: tumor volume = 1/2 x (width)2 x length. At the end of 8 wk, mice were killed by CO2 inhalation, and tumor tissues and nontumor tissues at the site of prostate cancer cell injection were dissected, measured, and evaluated histopathologically.

    Inhibition of tumorigenesis. DU145 cells were grown in 25-cm2 flasks and treated with 20 µmol/L lycopene for 5 d. The cells were digested by trypsin-EDTA, washed with PBS, and resuspended in F-12 medium at a concentration of 1 x 107 cells/100 µL Matrigel matrix. Male 5-wk-old BALB/c nude mice (n = 8) were injected s.c. with 100 µL of the lycopene-treated cell/Matrigel matrix on the left side of the dorsal surface. The right side was injected s.c. with an equal amount (1 x 107 cells/100 µL) of untreated cell/Matrigel matrix and served as control. Both treated and untreated cells were recounted to make sure that an equal number of cells were injected. Mice were observed daily for formation of gross tumors at the injection site; at the end of 1 mo, mice were killed and tumor tissues were dissected, volume measured, and the histopathology evaluated.

    Data analyses. Data are presented as means ± SD. The effects of lycopene concentrations and incubation times on the viability of human prostate cancer cells were tested by a 2-way ANOVA and post hoc Dunnett’s and Bonferroni’s tests. The rate of apoptosis was tested using the {chi}2 test. Inhibition of tumor growth was analyzed either by the {chi}2 test for the rate of tumor induction or by one-way ANOVA and Dunnett’s procedure for tumor volume. All analyses were performed using the SPSS 11.0 software. Differences with P < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Viability of human prostate cancer cells. The inhibitory effects of various concentrations of lycopene on the growth of 3 prostate cancer cell lines, DU145, PC-3, and LNCaP, and the time course effects are shown in Figure 1A–C. No significant inhibitory or stimulating effects on growth were found in any of these cell lines treated with lycopene at concentrations up to 50 µmol/L for the first 24 h. However, significant inhibition was observed in DU145 (Fig. 1A) and PC-3 cells (Fig. 1B) treated with lycopene from 48 to 96 h. Lycopene at ≥20 µmol/L inhibited DU145 and PC-3 growth at 96 h (P < 0.01) compared with control cells or cells treated with lycopene for 24 h (P < 0.01) (Fig. 1D). After 96 h, lycopene more potently inhibited the growth of the androgen-independent DU145 and PC-3 cells than the androgen-dependent LNCaP cells (P < 0.01) (Fig. 1D). The 50% inhibitory concentration of lycopene for these cell lines at 96 h was 26.6 µmol/L for DU145, 40.3 µmol/L for PC-3, and 168.5 µmol for LNCaP.



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  		FIGURE 1 The effect of lycopene on the in vitro viability of human prostate cancer cells, DU145 (A), PC-3 (B), LNCaP (C), and all 3 cell lines at 96 h (D), as determined by the MTT assay. Cells were seeded and cultured for 24 h and then treated with various concentrations of lycopene for 24, 48, 72, and 96 h. Data are expressed as the percentage of the value of the control culture treated with vehicle (THF). Values are means ± SD, n = 4. Replicate experiments yielded similar results. Asterisks indicate a difference from means at 24 h (A, B, C) and from LNCaP cells (D): *P < 0.05, **P < 0.01.

 
    Growth arrest and apoptosis in DU145 cells. Flow cytometry revealed that treatment with lycopene from 4 to 32 µmol/L for 48 h caused DU145 cells to accumulate in the G0/G1 phase of the cell cycle and undergo apoptosis in a dose-dependent manner (Fig. 2). Treatment with lycopene at 32 µmol/L for 48 h increased cells in the G0/G1 phase (P < 0.05) and in the G2/M phase (P < 0.01) compared with untreated controls (Table 1). The apoptosis rate, as demonstrated by the increase in the sub-G1 phase in Figure 2 and summarized in Table 1, was increased by treatment with 8–32 µmol/L; in cells treated with 32 µmol/L lycopene, the rate was 42.4% greater than in controls, P < 0.01.



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  		FIGURE 2 Inhibition of cell cycle progression and apoptosis in DU145 cells by lycopene. Cell cycle progression (phases of G0/G1, S, and G2/M) and apoptosis (subG1 phase) was measured by flow cytometry. The distribution of cells in different phases of the cell cycle: (A) THF alone, (B) 4 µmol/L lycopene, (C) 8 µmol/L lycopene, (D) 16 µmol/L lycopene, and (E) 32 µmol/L lycopene.

 

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  		TABLE 1 Effects of lycopene on cell cycle distribution and the rate of apoptosis in DU145 cells1

 
    DU145 tumor xenografts in nude mice. The inhibitory effect of lycopene was further evaluated by examining the growth rate of DU145 tumor xenografts in BALB/c male nude mice. Body weight gains did not differ between treated and control mice during the 8-wk experiment. No significant inhibition was found in wk 1 and 2 of treatment with lycopene; however, significant inhibitory effects on the tumor growth were observed after 3 wk of treatment (P < 0.05; Fig. 3). At the end of the 8-wk study, the rate of tumor growth was 55.6 and 75.8% lower (P < 0.01) in mice treated with 100 and 300 mg/kg lycopene compared with untreated controls (Table 2). Tumor volume in the lycopene-treated groups after 8 wk was 337.8 mm3 for 10 mg/kg (P = 0.153), 275.8 mm3 for 100 mg/mg (P < 0.05), and 112.63 mm3 for 300 mg/kg (P < 0.01), respectively, compared with 590.8 mm3 for vehicle-treated controls.



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  		FIGURE 3 Inhibitory effect of lycopene on tumor growth. BALB/c nude mice were injected s.c. with 100 µL (1 x 107) of DU 145 cells on the dorsal surface. After 24 h, lycopene (0, 10, 100, and 300 mg/kg) was administered 5 d/wk for 8 wk. Values are means ± SD, n = 15. Asterisks indicate a difference from the control: *P < 0.05, **P < 0.01.

 

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  		TABLE 2 Inhibitory effect of lycopene on growth of DU145 tumor xenografts in BALB/c nude mice1

 
    DU145 tumorigenicity. No tumor formed on the left side of the dorsal surface of the BALB/c nude mice with lycopene-pretreated DU145 cells. However, tumors formed on the right side where untreated cells were injected. Tumors usually formed 2 wk after the initial injection with untreated DU145 cells; even after 1 mo, no tumor had formed when lycopene-treated DU145 cells were injected.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
We studied the inhibitory effects of lycopene on the proliferation of 3 different human prostate carcinoma cell lines, including androgen-independent prostate DU145 and PC-3 cancer cells and androgen-dependent prostate LNCaP cancer cells. Natural lycopene inhibited the growth of all 3 prostate cancer cells and more potently inhibited the growth of the androgen-independent DU145 and PC-3 cells than the androgen-dependent LNCaP cells. The inhibition depended on the concentration of lycopene used and the duration of the treatment. No significant growth inhibitory or stimulating effects were found in cells treated with various concentrations of lycopene in the first 24 h. These results agree with previous reports that lycopene reduced the cell viability of these prostate cancer cells after extended treatment for ≥48 h (22,23). The more inhibitory effect on androgen-independent prostate cancer cells found in this study is also consistent with the epidemiologic and clinical observations that lycopene has an inhibitory effect on advanced and aggressive prostate cancers (4).

As observed in this study, oral administration of lycopene for ≥3 wk significantly inhibited the growth of DU145 tumor xenografts in BALB/c nude mice. This result suggests that lycopene acts mainly on the stages of tumor promotion and progression, in addition to its potent antioxidant properties, which is consistent with in vitro findings on growth inhibition in this cell line. Furthermore, lycopene-treated DU145 cells did not induce tumors as did untreated cells, strongly suggesting that lycopene may not only inhibit the growth of cancer cells, but also might induce differentiation or apoptosis in a stage-specific manner.

Many molecular targets, involved mainly in carcinogen metabolism, hormonal regulation, the cell cycle, apoptosis, DNA repair, cell signaling, and differentiation, were reported to be independently associated with human prostatic carcinogenesis (5,6). Although the mechanisms by which lycopene inhibits the growth of human prostate cancer cells are not well understood, protection against oxidative damage, induction of cellular communication through gap-junction, and modulation of cellular processes controlling cell growth are considered to be possible mechanisms of lycopene action (9,22). The suppression of the proliferation of prostate DU145 cancer cells found in this study may be due in part to the direct effects of lycopene on cellular processes controlling cell growth and the induction of apoptosis. Lycopene induced growth arrest in the DU145 cells by increasing the accumulation of cells in the G0/G1 phase, which was also consistent with the recent finding that lycopene inhibited cyclin D1 expression in G0/G1-arrested normal prostate epithelial cells (24). Apoptosis rate, as demonstrated by an increase in the subG1 phase and decreasing DNA content in the G2/M phase, was affected by lycopene treatment in a dose-dependent manner. This suggests that lycopene, like many other chemopreventive agents (3), follows a similar mechanism in inducing cell growth arrest and apoptosis. Molecular targets of lycopene in cell cycle check-points and pathways of apoptosis in different stages of prostate cancer cells will be investigated.

In summary, we found a potent inhibitory effect of lycopene on the growth of prostate cancer cells, especially the growth of androgen-independent prostate cancer cells, which supports our hypothesis that the inhibitory effect of lycopene on prostate cancer is specific to the stage of carcinogenesis. Results of this study also support epidemiologic findings that lycopene is an effective chemopreventive agent for human prostate cancer and may contribute to the reduced prostate cancer risk observed in individuals who consume large amounts of tomato-based, lycopene-rich food (5,6).


   ACKNOWLEDGMENTS
 
The authors thank Professor Xiaoling Ding of Southern Yangtze University College of Food Science and Technology, Wuxi, China for providing purified natural lycopene.


   FOOTNOTES
 
1 Supported in part by research grants CA 94683 and CA 90997 from the National Cancer Institute and research contract DAAD13–02-C-0070 (to J.-S.W.) from the Research Development and Engineer Command (RDECOM), United States Department of Defense. Back

Manuscript received 12 April 2004. Initial review completed 5 May 2004. Revision accepted 29 October 2004.


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