Carcinogenesis

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Carcinogenesis, Vol. 22, No. 3, 467-472, March 2001
© 2001 Oxford University Press

CARCINOGENESIS

Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis

K. Imaida^1,5, S. Tamano¹, K. Kato¹, Y. Ikeda¹, M. Asamoto¹, S. Takahashi¹, Z. Nir², M. Murakoshi³, H. Nishino⁴ and T. Shirai¹

¹ 1st Department of Pathology Nagoya City University Medical School, 1-Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan,
² LycoRed Natural Products Industries Ltd, Beer-Sheva 84102, Israel,
³ Lion Corp., 7-13-12 Hirai, Edogawa-ku, Tokyo 132-0035, Japan and
⁴ Department of Biochemistry, Kyoto Prefectural University of Medicine, Kajii-cho, Kawaramachidori, Kyoto 602-8566, Japan

	Abstract

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The chemopreventive efficacy of lycopene and curcumin with regard to prostate carcinogenesis was investigated using 3,2'-dimethyl-4-aminobiphenol (DMAB)- and 2-amino-1-methylimidazo[4,5-b]pyridine (PhIP)-induced rat ventral prostate cancer models. Three 60 week experiments with male F344 rats were carried out. In the first DMAB was given for the first 20 weeks and lycopene or curcumin were administered concomitantly or subsequently at dietary doses of 15 and 500 p.p.m., respectively. In the second experiment lycopene and curcumin were given to rats pretreated with DMAB at doses of 5, 15 or 45 p.p.m. or 100 or 500 p.p.m. In the third PhIP was selected as an initiator for prostate carcinogenesis and administered for 20 weeks. Rats were then fed a diet containing lycopene at a dose of 45 p.p.m. or curcumin at a dose of 500 p.p.m. or both together. Chemopreventive effects of lycopene and curcumin on development of DMAB-induced ventral prostate carcinomas were observed only in the first experiment and no confirmation of inhibition potential was obtained in the following studies. Neither summational nor synergistic chemoprevention was evident. It is concluded from the present data that, overall, neither lycopene nor curcumin can consistently prevent rat prostate carcinogenesis.

Abbreviations: BrdU, bromodeoxyuridine; DMAB, 3,2'-dimethyl-4-aminobiphenol; PCNA, proliferating cell nuclear antigen; PGs, prostaglandins; PhIP, 2-amino-1-methylimidazo[4,5-b]pyridine; PIN, prostate intraepithelial neoplasia.

	Introduction

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Causal factors for prostate cancer largely remain to be identified. However, epidemiological studies have suggested that foodstuffs are major factors. For example, mortality rates from prostate cancer in Japanese immigrants in areas of the USA such as Hawaii or California have been shown to be significantly increased whereas stomach cancer is reduced as compared with the of levels in Japanese in Japan (1,2). Among dietary factors, animal fat, retinol and carotenoids have so far been suggested to influence prostate cancer risk (3,4). Vitamin A and retinol are associated with normal control of both cellular differentiation and proliferation and various retinoids have been demonstrated to have the ability to inhibit carcinogenesis in animal models (5). An inverse association between retinoid intake and prostate cancer has been found epidemiologically (6). Recently, a large-scale epidemiological study revealed that consumption of lycopene, a non-provitamin A carotenoid, is also linked with reduced prostate cancer risk (7). The same group have shown an inverse association with elevated plasma lycopene (8,9).

Experimentally retinoic acid has been reported to have an inhibitory effect on N-methylnitrosourea plus testosterone-induced rat prostate carcinogenesis (10). On the other hand, lycopene was found to inhibit carcinogenesis in mouse mammary glands (11) and lung (12,13) and rat liver (14).

Curcumin is a major component of turmeric, the dried rhizome of Curcuma longa L., which is commonly used as a yellow coloring and flavoring agent in food in Asian countries. Curcumin has shown anticarcinogenic activity in rat colon (15) and mouse skin (16), lung (13) and mammary gland (17,18).

In the present investigation we have evaluated the chemopreventive effects of lycopene and curcumin on 3,2'-dimethyl-4-aminobiphenol (DMAB)- and 2-amino-1-methylimidazo[4,5-b]pyridine (PhIP)-induced rat ventral prostate carcinogenesis (19,20).

	Materials and methods

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The animals used were 6-week-old male F344 rats purchased from Charles River Japan (Kanagawa, Japan), weighing ~120 g at the beginning of the three experiments. Rats were housed in plastic cages on hardwood chips in an air conditioned room with a 12 h/12 h light–dark cycle and given food (Oriental MF; Oriental Yeast Co. Ltd, Tokyo, Japan) and water ad libitum. DMAB was obtained from the NARD Institute Ltd (Osaka, Japan). Lycopene (99.9%) (LycoRed Ltd, Beer-Sheva, Israel) and curcumin (Nacalai Tesque, Kyoto, Japan) were incorporated in the basal diet at the doses indicated.

Experiment 1
Animals were divided into seven groups; group 1 (25 rats) and groups 2–5 (20 rats each) were given DMAB s.c. at a dose of 50 mg/kg body wt 10 times at 2 week intervals (Figure 1). Groups 2 and 3 were administered a diet containing pure lycopene at a dose of 15 p.p.m. or curcumin at 500 p.p.m. for the first 20 weeks, concurrent with the carcinogen exposure. Groups 4 and 5 were given one of the supplemented diets starting just after treatment with DMAB until the end of the experiment. Groups 6 and 7 received only lycopene or curcumin without DMAB for the entire experimental period.

View larger version (24K): [in this window] [in a new window]   Fig. 1. Experimental protocol for Experiment 1. Animals were 6-week-old male F344 rats. Stippled, 50 mg/kg body wt DMAB by s.c. injection biweekly; cross-hatched, lycopene in the diet (15 p.p.m.) (LycoRed) or curcumin in the diet (500 p.p.m.) (Nacalai Tesque).

 
Experiment 2
To confirm the results of experiment 1, a second experiment to assess the dose dependence of lycopene and curcumin influence was performed. Six groups of rats (20 each ) were given DMAB for the first 20 weeks on the same schedule as described for experiment 1. Thereafter lycopene was given at doses of 5, 15 or 45 p.p.m. or curcumin at doses of 100 or 500 p.p.m. for 40 weeks. Levels of lycopene in the liver and serum of selected rats (three each for groups 1–4) at the end of the experiment were estimated individually according to the method of Oshima et al. (21).

Experiment 3
A total of 105 rats were divided into seven groups, 20 animals each for groups 1–4 and 15 each for groups 5–7. Prostate tumorigenesis was initiated by intragastric administration of PhIP twice a week at a dose of 100 mg/kg body wt and then rats were given lycopene (45 p.p.m.), curcumin (500 p.p.m.) or lycopene plus curcumin for 50 weeks (Figure 2).

View larger version (49K): [in this window] [in a new window]   Fig. 2. Experimental protocol for Experiment 3. Animals were 6-week-old male F344 rats. Stippled, 100 mg/kg body wt PhIP intragastrally twice a week; widely spaced cross-hatching, lycopene in the diet (15 p.p.m.); mid-spaced cross-hatching, curcumin in the diet (500 p.p.m.); closely spaced cross-hatching, lycopene (15 p.p.m.) and curcumin (500 p.p.m.) in the diet.

 
All three experiments were terminated 60 weeks after the start and surviving animals were killed by collecting blood from the aorta under light ether anesthesia and underwent complete autopsy. Rats that died or became moribund at earlier time points were also autopsied. All accessory sex organs were examined for gross abnormalities and fixed in 10% buffered formalin. For tissue preparation two sagittal slices through the ventral prostate and three through the dorsolateral prostate, including the urethra, as well as four transverse slices from each seminal vesicle, including the anterior prostate, were embedded in paraffin. Sections were cut at 4 µm and stained with hematoxylin and eosin for histopathological examination.

All animal experiments were performed under protocols approved by the Institutional Animal Care and Use Committee of Nagoya City University Medical School.

	Results

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Experiment 1
There were no differences in body weight gain, final body weights or survival rates among groups. Total amounts of lycopene and curcumin consumed per animal were 28 and 1040 mg for groups 2 and 3, respectively, 56 and 1943 mg for groups 4 and 5 and 84 and 3058 mg for groups 6 and 7. These values were calculated from average food intakes and the dietary concentrations. No clear adverse effects of lycopene or curcumin were observed throughout the experiment.

Data for preneoplastic and neoplastic changes in the male accessory sex organs are summarized in Table I. Lesions were confined to the ventral prostate and seminal vesicles, these being atypical hyperplasias and adenocarcinomas, as reported previously (22,23). The term atypical hyperplasia of the prostate was replaced by prostate intraepithelial neoplasia (PIN), that preferentially used in human prostate for premalignant lesions (24,25). The term atypical hyperplasia of the seminal vesicles was replaced with dysplasia. Concomitant administration of lycopene or curcumin with DMAB appeared to be associated with reduced development of lesions in the ventral prostate, but the differences were not statistically significant. Lycopene when given after initiation with DMAB decreased the incidences of PIN and carcinoma of the ventral prostate (P < 0.05) and curcumin markedly inhibited the appearance of prostate carcinoma (P < 0.02). Lycopene also decreased the numbers of dysplasias of the seminal vesicle (Table I).

View this table: [in this window] [in a new window]   Table I. Incidences and frequences of atypical hyperplasias and carcinomas of the ventral prostate and seminal vesicles (Experiment 1)

 
Immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) revealed labeling indices of the ventral prostate epithelial cells to be clearly suppressed by lycopene and curcumin (Figure 3, P < 0.01).

View larger version (18K): [in this window] [in a new window]   Fig. 3. PCNA labeling indices for prostate epithelial cells of rats given lycopene or curcumin after pre-treatment with DMAB in Experiment 1. **Significantly different from the DMAB alone group value at P<0.01.

 
Tumors in organs other than the prostate and seminal vesicles were located in the lung and intestine, but the incidences of those tumors were not influenced by either lycopene or curcumin, except that lycopene when given after DMAB increased lung tumor incidence (Table II).

View this table: [in this window] [in a new window]   Table II. Tumor incidences for organs other than the prostate (Experiment 1)

 
Experiment 2
In the dose–response experiment lycopene and curcumin given after treatment with DMAB did not significantly alter final body weights or liver, kidney or prostate weights (data not shown). Average food intake was almost the same in all groups. Lycopene concentrations in the livers of rats increased proportionally with dose (Table III). Serum testosterone levels did not clearly differ among the groups. Data for incidence of focal changes in the ventral prostate and seminal vesicles are summarized in Table IV. Significant modification was not demonstrated at any dose of lycopene or curcumin. The incidence of ventral prostate carcinomas was slightly suppressed by 45 p.p.m. lycopene, but this was not statistically significant. In contrast to the findings for the prostate, development of adenocarcinomas of the small intestine was increased by 45p.p.m. lycopene and 100p.p.m. curcumin (Table V).

View this table: [in this window] [in a new window]   Table III. Lycopene concentrations in the liver and serum (Experiment 2)

 

View this table: [in this window] [in a new window]   Table IV. Incidences of PIN and carcinomas of the ventral prostate and dysplasia of the seminal vesicles of rats given DMAB followed by lycopene or curcumin (Experiment 2)

 

View this table: [in this window] [in a new window]   Table V. Tumor incidences in organs other than the prostate (Experiment 2)

 
Bromodeoxyuridine (BrdU) labeling indices at the termination of the experiment in five rats of each group indicated that neither lycopene nor curcumin suppressed proliferation of ventral prostate epithelial cells (Figure 4).

View larger version (41K): [in this window] [in a new window]   Fig. 4. BrdU labeling indices in ventral prostate epithelial cells of rats treated with DMAB and then lycopene or curcumin. BrdU was given as a single i.p. injection 1 h before death. At least 1000 cells were counted and data are percentages (Experiment 2).

 
Experiment 3
Administration of 100 p.p.m. PhIP suppressed body weight gain by ~37% at week 10, but thereafter body weights gradually increased and subsequent treatment with lycopene and/or curcumin did not alter animal growth. There were no differences in final body weights or those of the liver, kidney and prostate. Neoplastic lesions in the accessory sex organs induced by PhIP were confined to the ventral prostate and seminal vesicles, as seen in the case of DMAB (19,20,26). As demonstrated in Table VI, the incidences of PIN in the ventral prostate and seminal vesicle dysplasia and the incidences and numbers of carcinomas of the ventral prostate were unaffected by either lycopene or curcumin. No summational or synergistic effects on prostate tumor development were evident with the two agents in combination (Table VII). There were no lesions in the prostate in groups 5–7, which did not receive PhIP. No modification of development of lung adenomas and colon adenomas/adenocarcinomas by lycopene and curcumin was noted (Table VIII). Serum testosterone levels among the groups did not differ significantly (data not shown).

View this table: [in this window] [in a new window]   Table VI. Incidences of proliferative lesions of the prostate and seminal vesicles (Experiment 3)

 

View this table: [in this window] [in a new window]   Table VII. Numbers of PIN and carcinoma in the ventral prostate (Experiment 3)

 

View this table: [in this window] [in a new window]   Table VIII. Tumors of the lung and large intestine (Experiment 3)

 

	Discussion

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The aim of the present series of experiments was to examine the chemopreventive potencies of lycopene and curcumin with regard to rat prostate carcinogenesis. In the three animal experiments initiated with DMAB or PhIP the induced carcinomas were confined to the ventral prostate and histopathologically were of non-invasive type. Lycopene exhibited chemopreventive effects in the first study, particularly when given in the post-initiation phase, but no reproducibility was evident in the following two experiments. The doses of lycopene were chosen on the basis of previously published data (27) and the concept that lower doses are relevant to human use. The data on cell proliferation, evaluated in terms of nuclear PCNA expression, provided support for tumor inhibition, but in the second experiment, even the highest dose of 45 p.p.m. had no effects. In the case of curcumin, although an inhibitory influence on DMAB-induced prostate carcinogenesis was demonstrated in the first experiment, no confirmation could be subsequently obtained. Thus, it is possible that the suppression observed in the first experiment was fortuitous.

Lycopene at a dose as low as 0.5 p.p.m. has been reported to inhibit appearance of spontaneous mammary tumors (11). However, there are also some studies that failed to demonstrate anticancer efficacy (12,28–30) in the liver, colon, urinary bladder and lung. Narisawa et al. found that although lycopene itself did not inhibit rat colon carcinogenesis (the end marker being the appearance of aberrant crypt foci), tomato juice was effective (27). A study by Okajima et al. also demonstrated carcinogenesis suppression effects only when lycopene was combined with piroxicam and/or ß-carotene (28). Thus, there are conflicting data regarding the biological effects of lycopene as a chemopreventor.

Giovannucci et al. have reported that lycopene intake is related to a lower risk of non-stage A1 prostate cancer (7) in US males, with tomato sauce, tomatoes and pizza as the primary sources. They concluded that lycopene and other compounds in tomatoes might reduce prostate cancer risk. Intake of the carotenoids ß-carotene, -carotene, lutein and ß-cryptoxanthin were not linked with the risk of prostate cancer. Furthermore, the same group showed that elevation of plasma lycopene levels was associated with lower prostate cancer risk (8). Reviewing 72 epidemiological studies of intake of tomatoes and tomato-based products, Giovannucci found that 35 showed a statistically significant inverse association between tomato intake and blood lycopene level and the risk of cancer at defined anatomical sites (9). The prostate was the site with the strongest benefit, followed by the lung and the stomach. As human trials with ß-carotene revealed that exessive ß-carotene intake increased lung cancer risk, especially for smokers, it is possible that excessive carotenoid intake may increase lung cancer risk, especially for smokers. Although Giovannucci's study (9) did not detect any risk to smokers of lycopene intake, it is possible that excessive lycopene intake may increase human lung cancer risk for smokers, since the present study showed that lycopene increased lung cancer incidence in rats.

A variety of other organs, such as the pancreas, colon, rectum, esophagus, oral cavity, breast and cervix were listed as suggested sites of benefit. However, there is no concrete evidence that lycopene itself was the responsible agent and there is a distinct possibility that numerous other beneficial components may contribute to the anticancer properties of tomatoes. Therefore, as a more representative method, studies of rat prostate carcinogenesis should be made with tomato products such as tomato juice. We should also pay attention to altered intake of other dietary factors with preferential consumption of tomatoes and their products.

Curcumin is a widely used dietary pigment and spice that has been demonstrated to be an effective inhibitor of tumor promotion in many in vivo experimental studies (15,17,32–38). Tanaka et al. reported that a dose of 500 p.p.m. was effective against rat tongue carcinogenesis (33). However, in many other experiments chemopreventive effects were only evident when very high doses were used. From the practical viewpoint these cannot be attained in the human situation and we therefore selected a dose of 500 p.p.m., at which no consistent chemopreventive effects on prostate carcinogenesis were evident. As found by Pereira et al., there may be organ specificity in the chemopreventive effects of curcumin (15). Unlike lycopene, a literature survey failed to uncover any epidemiological studies investigating the relationship between curcumin intake and incidence of or mortality due to any type of malignancy.

In addition to prostate tumors, DMAB induces lesions in other organs, such as Zymbal gland tumors and preputial gland tumors, which frequently affect survival rates. In terms of models for prostate carcinogenesis, PhIP can be considered to be a better selection as a carcinogen. In the present three experiments development of colon tumors occurred in DMAB- and PhIP-treated groups, but alterations in their incidences were not observed with either lycopene or curcumin, although feeding of the latter at a dose of 2000 p.p.m. has been shown to inhibit biosynthesis of prostaglandins (PGs) such as PGF₂ and PGD₂ in rat colon mucosa (37). The lower dose of curcumin in the present studies may account for the negative result regarding colon tumor suppression. In a previous study in our laboratory, however, the anti-inflammatory drug indomethacin decreased PGE₂ but did not suppress the development of DMAB-induced rat ventral carcinomas (39).

In conclusion, lycopene and curcumin did not exhibit consistent chemopreventive effects against DMAB- or PhIP-induced rat prostate carcinogenesis in the present series of experiments. Since epidemiological studies have strongly indicated an inverse relationship between incidence of prostate cancer and intake of lycopene in tomato or tomato juice, interactions with other components need to be assessed in further in vivo experiments to explore the beneficial effects on prostate carcinogenesis.

	Notes

 
⁵ To whom correspondence should be addressedEmail: imaida{at}med.nagoya-cu.ac.jp

	Acknowledgments

 
This work was supported in part by a grant-in-aid from the Ministry of Health and Welfare for the Second-Term Comprehensive 10-Year Strategy for Cancer Control, Japan, a grant-in-aid from the Ministry of Education, Science, Sports and Culture, a grant-in-aid from the Ministry of Agriculture, Forestry and Fisheries and a grant from the Society for Promotion of Toxicological Pathology of Nagoya, Japan.

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Received July 28, 2000; revised November 16, 2000; accepted November 22, 2000.

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