Chapter 4
Lycopene and Cancer: An Overview
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Joseph Levy, Michael Danilenko, Michael Karas, Hadar Amir, Amit Nahum, Yudit Giat, and Yoav Sharoni Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev and Soroka Medical Center of Kupat Holim, Beer-Sheva 84105, Israel
The remarkable association between diets rich in fruits and vegetables and the reduced risk of several malignancies has led to a consideration of the role of carotenoids in this context. Lycopene is one of the major carotenoids in Western diets and accounts for about 50% of carotenoids in human serum. The interest in the anticancer action of this particular carotenoid is relatively recent and can be explained by several reasons: a. Among the common dietary carotenoids lycopene has the highest singlet oxygen quenching capacity and a high capability of quenching other free radicals in vitro. b. The inverse relationship between lycopene intake or serum values and cancer risk that has been observed in particular for cancers of the prostate, pancreas, bladder and cervix. c. Laboratory findings demonstrate that lycopene inhibits cancer cell growth in vivo and in vitro (in some cases independently of their role as antioxidants). d. New evidence has provided a mechanistic explanation for the anticancer activity of lycopene. Nutrition and absorption of lycopene. Since mammals cannot synthesize carotenoids, including lycopene, these pigments are obtained mainly from vegetables and fruits. In contrast to α-carotene, β-carotene, lutein and zeaxanthin, which are widely distributed among a great variety of fruits and vegetables, lycopene enters the diet predominantly in tomatoes and tomato products. These include popular dishes such as chili con-carne, pizza or spaghetti with tomato sauce. Because of the frequency of consumption, tomato ketchup is also a major contributor of lycopene in many diets (1). The loss of lycopene during food preparation, such as cooking, is minimal. In fact, bioavailability of lycopene can be greatly improved by heating with the addition of some fat, as has been demonstrated by Stahl and Sies (2). In Western countries lycopene is the major carotenoid in human plasma; its concentration (-0.8 μΜ) is more than twice that of β-carotene or the sum of lutein and zeaxantin together. This may result from either its high intake in the diet or its long
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©1998 American Chemical Society
Shibamoto et al.; Functional Foods for Disease Prevention I ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 6, 2017 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0701.ch004
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half-life in the body. The latter suggests that its frequent supply in the diet may not be contributory, but Micozzi (3) has stressed the importance of frequent intake of lycopene. Healthy subjects under strict carotenoid intake regimens were studied. Lycopene blood levels, but not those of a-and β-carotene or lutein, fell significantly during the 60 day follow-up when a carotenoid diet was not supplied. This suggests that plasma carotenoid concentrations, other than lycopene, remain fairly constant and are slow to change with low dietary intake. In another similar study (4), the fall in the plasma lycopene level was accompanied by a fall of other major carotenoids in the plasma. The reasons for the discrepancy between these two studies are not clear. Nevertheless, the two studies reported a steep fall in lycopene plasma levels in subjects with a low carotenoid diet. Of the different geometrical isomers of lycopene, the cis isomers (9-and 13-cys) are better absorbed than the all-trans form (2). The absorption and distribution of [ C]lycopene were studied in rats and in rhesus monkeys following the oral administration of the carotenoid in olive oil. The liver contained the largest amount of radioactive pigment. No labeled metabolic products of lycopene were found (5). 14
Physiological and pathological conditions which may affect lycopene serum levels. The fact that age and stress significantly reduce lycopene serum levels indicates the appropriateness of specific populations for supplementation programs. A recent study was undertaken to characterize plasma concentrations of α-tocopherol, lycopene, βcarotene and several other carotenoids in elderly subjects. The test population consisted of 94 participants, 77 - 99 years old accrued from a project known as the Nun Study, (a longitudinal study of aging and Alzheimer disease patients). Concentrations of all analytes, except lycopene, were similar to or higher than those reported for several middle-aged American populations. Lycopene concentrations were significantly lower in the nun population as compared with the middle-aged populations and tended to decrease across age groups (6). In another study, which tested age-dependent changes in antioxidant plasma levels in a high risk stomach cancer population (1,364 subjects 35-69 years of age), lycopene was the only antioxidant whose level decreased significantly (7). Investigation was carried out to determine whether the acute phase response is associated with suppressed circulating levels of antioxidants in a population of 85 Catholic sisters 77-99 years of age (Nun Study). It was clearly demonstrated that such physiological conditions are associated with decreased plasma levels of the antioxidants lycopene, α-carotene, and β-carotene. The authors concluded that this decrease in circulating antioxidants may further compromise antioxidant status and increase oxidative stress and damage in the eldery (8). Another recognized age-related pathology is macular degeneration. It is well documented that lutein and zeaxanthin are the main carotenoids in the eye macula. A study was designed to investigate the relationship between tocopherol levels and various carotenoids in the serum with age-related macular degeneration. Cases included 167 patients with various related pathologies and an equal number of ν controls. The surprising results show that the average levels of most carotenoids, including those composing macular pigment (lutein and zeaxanthin), were similar in cases and controls. However, persons with levels of lycopene in the lowest quintile were twice as likely to have age-related macular degeneration. The authors concluded that very low levels of lycopene, but not other dietary carotenoids or tocopherols, are related to age-related macular degeneration (9).
Shibamoto et al.; Functional Foods for Disease Prevention I ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
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Lycopene as an antioxidant. Reactive oxygen species occur in tissues and can damage D N A , proteins, carbohydrates and lipids. Lycopene exhibits the highest physical quenching rate constant with singlet oxygen (10). In a recent study (11), the ability of β-carotene to quench ΝΟΟ· radicals was compared to that of lycopene. ΝΟΟ· radicals are present in tobacco smoke and may cause cancer by reacting with various cell components. Cell staining with trypan blue was used to follow cell death. It was found that lycopene was at least three-fold more effective than β-carotene in preventing cell death by quenching of ΝΟΟ· radicals. Smedman et al. (12) have reported that lycopene protects D N A damage in colon cells induced by 1-methyl 3-nitro-l-nitrosoguanidine (MNNG) and H2O2. The greatest protective effect was observed at a lycopene concentration approximating that found in blood of subjects consuming normal levels of tomatoes. The authors concluded that this effect cannot be explained simply by the antioxidant capacity of lycopene because the genotoxic effect of the alkylating agents, M N N G , was also inhibited. Epidemiological studies involving lycopene and cancer. Beta-carotene was extensively studied and implicated as a cancer preventive agent (see (13) for a review). However, intervention studies carried out with this carotenoid have revealed no beneficial effect (14,15) nor showed a negative effect (16,17). In the well-known Finnish study (16) almost 30,000 heavy smokers (all male) were followed for five to eight years in a randomized trial. An unexpectedly higher incidence of lung cancer was observed among men who received β-carotene than among those who did not. In another study (15) the efficacy of β-carotene in preventing colorectal adenoma (a precursor of invasive carcinoma) was tested in randomly assigned patients. From the results, it is clear that there is no evidence indicating that β-carotene reduces the incidence of adenomas. These results point out that dietary factors other than βcarotene may contribute to a reduction in cancer risk associated with a diet high in vegetable and fruits. No intervention trials in humans investigating the potential effect of lycopene supplementation on the prevention of cancer have been performed to date. At present, only epidemiological studies which examined data on lycopene intake (based on questionnaires) or lycopene plasma levels in relation to cancer risk are available. A study of cervical intra-epithelial neoplasia was designed to test the potential protective effects of various carotenoids (18). In this study, both dietary and serum lycopene manifested a strong inverse association with this malignancy. No such association was detected in the same study in regard to β-carotene intake. A lower level of serum lycopene was also observed in patients who subsequently developed bladder (19) and pancreatic (20) cancers. Serum levels of retinol, retinol-binding protein, and β-carotene were similar among cases and controls. A protective effect of vitamin-Α and β-carotene was found in squamous cell and small cell lung cancers. (21). In a later study, however, β-carotene-rich foods such as papaya, sweet potato, mango and yellow orange vegetables showed little influence on survival of lung cancer patients (22). The authors concluded that β-carotene intake before diagnosis of lung cancer does not affect the progression of the disease. In contrast, a tomato-rich diet which contributes only small amounts of β-carotene to the total carotenoid intake had a strong positive relationship with survival, particularly in women. In other studies however, lycopene intake was found to be unrelated to lung cancer risk(23,24). A significant trend in risk reduction of gastric cancers by high tomato consumption was observed in a study which estimated dietary intake in low risk versus high risk areas in Italy (25). It is interesting that a similar regional impact on
Shibamoto et al.; Functional Foods for Disease Prevention I ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 6, 2017 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0701.ch004
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stomach cancer risk was found also in Japan (26). Out of several micronutients including vitamins A , C and D and β-carotene in plasma, only lycopene was stronglyinversely associated with stomach cancer . A consistent pattern of protection for many sites of digestive tract cancer was associated with an increased intake of fresh tomatoes (27). Nevertheles, the possibility exists that other benefits of a Mediterranean life style get confused with high lycopene intake from a tomato rich diet. Various case control studies have examined the risk factors for breast cancer which are unrelated to lycopene intake or serum levels (28,29). No direct epidemiological data are available on the potential role of lycopene consumption in skin cancer. However, Mercado et al. (30) demonstrated that lycopene, but not βcarotene, levels decrease significantly in the area of U V irradiated skin. Recently, Giovannucci et al. (31) published a survey based on the U.S. Health Professional Follow-up Study.on prostatic cancer which included 48,000 people participatiants. This 7-year study showed that lycopene intake from tomato-based products is related to a low risk of prostate cancer. Consumption of other carotenoids (β-carotene, α-carotene, lutein, β-cryptoxantine) or retinol was not associated with the risk of prostate cancer. In vivo and in vitro evidence for the inhibition of cancer by lycopene The anticancer activity of carotenoids has been reviewed by Krinsky (32,33) and more recent reviews have specifically addressed the anticancer activity of lycopene (34,35). The effect of several retinoids and carotenoids, including lycopene and βcarotene, was tested on rat C-6 glioma cells (36). A l l the retinoids and carotenoids which were dissolved in D M S O inhibited cellular growth at the 10 μΜ range. Lycopene effects were similar to those of β-carotene. Another study by Wang's group (37) was performed on an in vivo model of glioma cells transplanted in rats. This study also demonstrated that lycopene is an effective inhibitor. More recently, Nagasawa and colleagues (38) found that lycopene inhibits spontaneous mammary tumor development in SHN virgin mice probably by modulating the immune system in tumor-bearing mice (39). The inhibitory effect of four carotenoids found in human blood and tissues which are effective against the formation of colonic aberrant crypt foci induced by N methylnitrosourea was examined in Sprague-Dawley rats (40). Lycopene, lutein, acarotene and palm carotenes (a mixture of alpha-carotene, beta-carotene and lycopene), but not beta-carotene, inhibited the development of aberrant crypt foci. The same research team also compared the cancer preventive effect of five kinds of carotenoids on mouse lung carcinogenesis with similar results (personal communication). Our laboratory also tested lycopene, in comparison to β-carotene, in a well-known animal model for hormone-dependent mammary cancer dimethyl benz(a)anthracene (DMBA)-induced rat mammary tumors (41). The carotenoids (10 mg/kg, i.p.) were administered twice a week. The number of tumors was higher in the control (noninjected group) and in the β-carotene-treated group, than in the lycopene group. In the latter, the difference was evident only at longer periods of time. The largest average size of tumors was found in the β-carotene group and the smallest average size was in the lycopene group. This difference is statistically significant (p
