1Department of Urology, St George's Hospital, London, UK
2Department of Biological Sciences, Imperial College, London, UK
Correspondence to: N J Barber, Department of Urology, St George's Hospital, Blackshaw Road, London SW17 0QT, UK"
| Abstract |
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| The role of diet and dietary supplements in the development and progression of prostate cancer represents an increasingly frequent topic of discussion in the urologist's office. As access to information becomes forever easier, patients are more aware and educated about this subject than ever before. The role of antioxidants including carotenoids in all this has been the subject of great interest for some time. Lycopene, the carotenoid that gives tomatoes and other fruits and vegetables their red colour, has been of particular interest recently as regards its role in prostate cancer. The aim of this review is to briefly outline the biology and chemistry of lycopene, the scientific basis for its proposed anticancer properties and evaluate what conclusions the practicing urologist may draw from the data thus far. The media and industry have raced to encourage not only diets high in lycopene but also dietary lycopene supplements but there is probably only sufficient evidence to recommend to patients a diet rich in all vegetables and fruits of which tomatoes and tomato based products should certainly be a part. Prostate Cancer and Prostatic Diseases (2002) 5, 6-12. DOI: 10.1038/sj/pcan/4500560 |
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| Keywords |
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| carotenoids; lycopene; prostate cancer |
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| Introduction In the twenty first century the public are increasingly more educated regarding health issues. With this comes a greater awareness of the incidence of prostate cancer in the population and inevitably, therefore, more interest in what lifestyle changes may help in the avoidance of this common disease. The incidence and mortality rates of prostate cancer vary geographically but are strongly associated with affluence and dietary factors related to affluence.1,2 Populations who migrate from low risk countries, for example Japan and Poland to the USA, suffer an increase risk of developing the disease.3,4 Furthermore, as previously low risk countries have become more westernized so the incidence of prostate cancer has risen.2 Around the world and particularly in the USA this has led to numerous epidemiological studies investigating the link between diet and all cancers including that of the prostate gland. To date a long list of dietary factors have been associated with the development of prostate cancer including fat, specific fatty acids, soy, calcium, various vegetables, lycopene and supplements of vitamin E, selenium, vitamin C and zinc. It was analysis of data from the Health Professionals Follow-Up (HPFU) study that first indicated a possible inverse relationship between the intake of lycopene and the risk of prostate cancer.5Not surprisingly, this has led to a great deal of enthusiasm for the recommendation of lycopene containing foodstuffs as a regular part of a healthy diet. Indeed, Heinz, for example, have established an intensive advertising campaign to promote their lycopene-rich products (Figure 1). There are now even numerous websites expounding the benefits of dietary lycopene, eg lycopene.com, lycopene¾advice.com, lycopene.org, lycored.com and tomatolycopene.com and even more advertising lycopene containing dietary supplements. Famously the departing Mayor of New York, Rudolph Giuliani, has also declared that he now eats large amounts of lycopene-rich plum tomatoes having been diagnosed with prostate cancer. In this review we hope to briefly outline the nature of lycopene, the scientific basis for its proposed anti cancer properties and discuss the evidence thus far as related to its role in the incidence of prostate cancer such that urologists may be better armed in the face of ever more knowledgeable and inquiring patients. |
The chemistry and biology of lycopene Lycopene is a member of a group of natural pigments known as carotenoids. Carotenoids are synthesized by both plants and micro-organisms and are widely found in the environment, giving, for example, the colours to many flowers, fruits and vegetables. Animals cannot synthesize carotenoids and rely on ingestion for their source of these molecules. In plants the principal function of this family is to serve as light absorbing pigments and also protect cells against photo-oxidative damage during the process of photosynthesis. For humans, carotenoids have a dietary role; principally that of beta-carotene, which serves as a source of vitamin A. Until recently less emphasis has been placed on the importance of lycopene as a dietary factor. While beta-carotene is orange and responsible for the colour of carrots for example, lycopene gives the red colour to tomatoes and other fruits such as guava, watermelon, pink grapefruit and papaya (see Table 1). In the Western world 85% or more of dietary lycopene comes from tomatoes and tomato based products. In the UK the average intake is about 1 mg which is lower than that estimated for the USA by about five times. Thus far, more than 600 carotenoids have been described and as a family they share common structural features. These include a number of centrally located conjugated double bonds and a polyisoprenoid structure. Lycopene itself is an acrylic and extremely hydrophobic carotenoid and is known to have 13 conjugated double bonds arranged in a linear fashion (Figure 2). It is a lack of a beta ionone ring that leaves lycopene free of provitamin A activity. The conjugated double bonds allow lycopene and indeed all carotenoids the ability to isomerize and thus numerous combinations of cisand trans isomers are possible. The most thermodynamically stable configuration is the all-trans configuration and it is this isomer of lycopene that is most commonly found in raw foods. However, cooking or other types of food processing can cause isomerization leading to increased levels of cis-isomers, particularly 5-cis.6 In biology, the absorption of light, exposure to energy (eg heat) or chemical reactions are thought to result in isomeric interconversion. In truth, little is known regarding the biology of dietary lycopene in the human gastrointestinal tract. It is assumed to follow a similar route of absorption as beta-carotene. It is likely, therefore, that lycopene is digested and absorbed in a pattern of events one would expect of a hydrophobic molecule or lipid, being acted upon by bile salts and pancreatic lipases and incorporated into micelles that are absorbed into the mucosal cells by a passive process. Thereafter, lycopene is transported from the gut mucosa by chylomicrons and later in the circulation the bulk of lycopene is found in the hydrophobic core of low density lipoproteins.7,8 Interestingly, lycopene, like other carotenoids, is found in tight protein-carotenoid complexes and crystalline aggregates in most foods leading to some significant barriers to economic absorption. These tight bonds are dissociated by heating leading to improved bioavailability and it is well recognized that heating tomato juice with lipid improves lycopene absorption.6 Under favourable conditions as much as 30% of lycopene can be absorbed with the rest being excreted. Once absorbed it is possible to measure serum concentrations of lycopene and it appears stable in collected blood samples stored at -70°C for many years.9,10 Whilst serum concentrations may vary hugely between different populations11,12,13,14,15,16,17,18,19,20 there appears to be much smaller changes in the serum within an individual unless significant changes in dietary intake occur; for both dietary restriction21 and addition22,23 of lycopene will have gradual effects on serum concentration. To measure the immediate effect of diet on lycopene absorption it is better to measure chylomicron lycopene content.24 Once in the circulation, lycopene is distributed to tissues around the body and it is becoming increasingly clear that this is not a uniform process. Significantly higher concentrations of lycopene, compared to the other carotenoids, are found in the liver, the adrenal glands, the testes and the prostate gland.14,25,26,27,28,29,30 Once again, however, the interpersonal variation of tissue lycopene content is large (up to 100-fold). The efficiency of the digestive and absorptive pathway from dietary intake of lycopene to absorption into the serum and transport to the tissues has not been widely investigated. Furthermore, there is significant variation in the types of isomers measured in the plasma as compared to prostate tissue. In foodstuffs approximately 5-10% of total lycopene appears as cis isomers as compared to about 50% in plasma and about 80% in prostate tissue.28,31,32The relative importance of this is not clear, particularly in any active biological role lycopene may play within the prostate. However, given thatcis isomers dissolve better in lipophilic solutions compared to trans isomeric forms, which tend to aggregate and crystallize, trans-membrane movement of the cis isomer into cells may be relatively facilitated. Lycopene does seem to be a major carotenoid in the prostate, however, the two studies that have examined this to date appear to differ as to relative quantities of the carotenoids found.28,33 In the more recent study,33 lycopene levels in the prostate tissue ranked third behind beta-carotene and lutein and this appeared to reflect relative plasma concentrations. This would tend to suggest that lycopene is not preferentially taken up by the prostate and that uptake from the plasma to prostate tissue is a passive process from the serum lipoproteins in which carotenoids are transported. Thus increased levels of lycopene in prostate tissue is expected when its plasma concentration is high due to a lycopene rich diet. |
Dietary sources of lycopene Lycopene is found in a relatively narrow range of foods and its content in these foodstuffs has been measured in a number of laboratories (Table 1).31,34,35,36 The principal source of dietary lycopene is undoubtedly tomatoes in most people's diets, however, lycopene content varies in different varieties of tomatoes and it is important to realize that tomatoes contain a whole different variety of carotenoids other than lycopene. Although sensitive to isomerization, lycopene is relatively stable when cooked.37,38 Indeed, as mentioned earlier, the bioavailability of lycopene appears to be enhanced by processing and cooking.6 Ingestion of tomato paste leads to greater rises in both serum chylomicron trans and cis isomers of lycopene compared to that of fresh tomatoes when both are given with corn oil to aid absorption.39 The accurate estimation of lycopene intake is dependent both on the accuracy of food frequency questionnaires and also on the food composition databases employed. Unfortunately significant quantitative differences in estimated lycopene intake may be observed if different databases are used in analyzing the results of the same food intake questionnaire although qualitatively individuals are similarly ranked in terms of high or low intake of lycopene.24 Thus, self reported food questionnaires and estimation of lycopene intake calculated from databases thereafter does appear to rank intake correctly40,41 but lacks quantitative accuracy. It does seem that such food questionnaires cannot be used confidently to estimate the lycopene (or indeed any carotenoid) content of the prostate however.33 Whether this conclusion of Freeman et al. reflects the small numbers in the study (n=47) or the methodology employed (particularly of tissue sampling) is open to question. The authors themselves held the self-report of dietary intake as the most likely source of any error. However, accurate data of lycopene content in cooked vegetables was not incorporated into a comprehensive database until 199842 and this was not used in this study, perhaps leading to another source of error. Other studies have demonstrated good associations between dietary carotenoid intake and plasma levels43 and, importantly, plasma levels of all the antioxidants measured did correlate well with prostatic tissue levels in this study. Further larger studies or well designed feeding studies or studies requiring more accurate dietary assessments will be required to demonstrate the relationship between lycopene intake and prostatic levels.44 Moreover, the important influence of other concurrent dietary factors on the efficiency of intestinal lycopene absorption need to be included in any database. |
Lycopene and the biology of cancer For some time the role of the oxidative damage to cellular protein, lipid and most importantly DNA has been proposed as a possible mechanism of the evolution of cancer, including prostate cancer.45,46 The oxidative weapons are free radicals, which are molecules with an unpaired electron on the outer shell. There are intrinsic defense mechanisms against cellular damage by these free radicals including the enzymes glutathoine peroxidase and superoxide dismutase. Not surprisingly, interest has developed in exogenous sources of antioxidants and these include vitamin E, vitamin A, selenium and carotenoids including lycopene.47 Carotenoids may react with oxygen free radicals by either transfer of the unpaired electron leaving the carotenoid in an excited triplet state, the excess energy being dissipated as heat, or by 'bleaching' of the carotenoid. The former leaves the carotenoid intact and therefore able to be involved in numerous cycles of free radical scavenging, the latter results in decomposition of the carotenoid. Fortunately, it is the former that predominates and the efficiency of this process seems to be related to the number of double bonds incorporated in the carotenoid structure. Interest has been heightened in lycopene, in particular, as it has a large number of double bonds and thus has been found to be the most potent scavenger of oxygen free radicals of all the carotenoids.48 Lycopene has been demonstrated to not only scavenge oxygen free radical species, for example peroxyl radicals, but also interact with reactive oxygen species such as hydrogen peroxide and nitrogen dioxide49,50,51 and in this manner protect cells from oxidative damage. Interestingly lycopene was found to be twice as efficient as beta-carotene in scavenging for nitrogen dioxide.49,52 Lycopene has also been demonstrated to have other possible anti cancer activities particularly relating to modulation of intercellular communication and alterations in intracellular signalling pathways.53 These include an upregulation in intercellular gap junctions,54 an increase in cellular differentiation55 and alterations in phosphorylation of some regulatory proteins.56 Little is known regarding the role or indeed importance of these effects in vivo, however, lycopene has been demonstrated to be significantly more efficient than any carotene in inhibiting insulin-like growth factor type 1 (IGF1) induced proliferation of a number of tumour cell lines57 and decrease the occurrence of both spontaneous and chemically induced mammary tumours in animal models.58,59 In prostate cancer, in particular, a study has demonstrated inhibition of cell line proliferation in the presence of physiological concentrations of lycopene in combination with alpha-tocopherol.60Interestingly, a large study has linked lower levels of IGF1 (high levels of which are associated with the incidence of prostate cancer61) with increased tomato intake in the diet.62 |
Lycopene and prostate cancer The interest in the possible anti cancer properties of carotenoids and more recently lycopene itself are based not only on a sound scientific basis, but also on a wealth of epidemiological data from around the world. Numerous studies have demonstrated associations of higher dietary fruit and vegetable intake with lower risks of a whole range of cancers. The strength of the evidence is such that the National Research Council of the Academy of Sciences,63 the National Cancer Institute64 and the World Cancer Research Fund and the American Institute for Cancer Research65 have all recommended increasing dietary intake of citrus fruits, cruciferous vegetables, green and yellow vegetables and fruit and vegetables high in vitamins A and C to lower cancer risk. Similar recommendations have been made by the UK government66 and by the World Health Organization.67However, it was analysis of data from the HPFU study that initially proposed the possible importance of relative intake of lycopene as opposed to other chemicals found in fruit and vegetables on the risk of prostate cancer.5 Of nearly 50 000 men, 812 developed prostate cancer. Of the dietary variables measured (including alpha- and beta-carotene) only lycopene was associated with a decreased risk (21%) of prostate cancer (age and energy adjusted RR=0.79; 95% confidence interval=0.64-0.99 for high vs low quintile intake). In this study high intake of tomatoes and tomato products (accounting for 82% of lycopene intake) reduced the total risk of prostate cancer by 35% and of high grade cancer by 53%. Those in the higher quintile were said to consume more than 10 servings of lycopene per week as opposed to less than one in the lower quintile. Perhaps related to changes in bioavailability as outlined above, it was also found that the consumption of tomato sauce as opposed to tomato juice has the strongest inverse association (RR=0.66, 95% confidence interval=0.49-0.90; P for trend=0.001). It is important to note that this study is one of some 17 studies5,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83 that has examined dietary carotenoid intake and the risk of prostate cancer and whilst two have found protective effects for beta-carotene only the study by Giovannuci et al 5 has shown an effect related to lycopene. Moreover, of the seven studies that specifically examined whether dietary tomato products in particular reduce the risk of prostate cancer, only three found this to be the case.5,84,85 One further is inconclusive statistically but tends to support that hypothesis86 and three found no association at all.73,87,88 However, one of the latter three negative studies73 did describe a strong dietary association of decreased risk of prostate cancer with the consumption of tinned baked beans (RR=0.52; 95% confidence interval=0.31-0.88) and the authors did suggest that tinned baked beans do provide a large amount of highly bioavailable lycopene. A number of studies have examined a similar association with plasma lycopene levels rather than dietary intake. Three have shown a negative association with the risk of prostate cancer89,90,91 and one showed no link.92In one study,89 a statistically non significant 6.2% lower median lycopene level was demonstrated in those who developed prostate cancer compared to age and race matched controls (RR=0.50 95%CI=0.20-1.29) between high and low quartiles of plasma lycopene and another (based on 581 subjects)90 a statistically significant RR of 0.56% (95%CI=0.34-0.91) was demonstrated when comparing high quintile with low quintile of plasma lycopene. In comparing both dietary studies and plasma studies one must remember the huge interpersonal and indeed intercultural differences in lycopene levels, as outlined above, and recognize that some of the unsupportive studies relate to populations with low base-line dietary intake and plasma levels.88,92 |
Conclusions In order to clarify the muddied waters as to whether any proposed association truly exists between ingestion of lycopene and reduced frequency of prostate cancer, further studies should aim to separate the effects of vegetables in general from that of tomatoes. It may be that lycopene merely represents a good marker of vegetable and fruit intake and that people who eat large quantities of fruit and vegetables tend to be those who are more health conscious and one could argue also avoid high cancer risk behavior anyway. On the other hand, those same health conscious people are more likely to seek 'screening' for prostate cancer and thus be diagnosed with the disease. It is also important to realize that lycopene rich foodstuffs are not necessarily linked to vegetable intake, such as ketchup, pizzas and tomato sauces and as such may be fairly viewed as a separate dietary factor from vegetable intake. Further studies should employ dietary questionnaires and nutrient databases that are specifically sensitive to lycopene.44 Of all the carotenoids, beta-carotene has been most investigated, particularly in relation to decreasing risk of smoking related cancers. It is important to note, however, that two trials of supplemental beta-carotene actually seemed to lead to an increased risk of lung cancer in male smokers of 28%93 and 18%94 in the treated vs untreated arms. The results of this study serve to warn that fruits and vegetables contain a whole range of biologically active substances and to choose one for dietary supplementation must be a carefully made decision based on good scientific data. One must therefore view with caution the potentially exciting results from the Karmanos Cancer Institute, Detroit.95 A prospective, single blind, placebo controlled, randomized study was performed where 15 of 26 men scheduled for radical prostatectomy for organ confined malignacy were given lycopene supplements, 15 mg twice a day (Lyc-O-MatoÔ, LycoRed, Beer-Sheva, Israel) for 3 weeks pre operatively. Serial measurements confirmed a 22% increase in plasma and tissue lycopene levels and a statistically significant fall in prostate specific antigen (PSA) over the 3 weeks in those taking lycopene. Those in the supplement arm were also found to have smaller volume tumours and surgical margins were less likely to be positive. Furthermore, analysis of the excised tissue showed that biomarkers of cellular proliferation decreased, whereas those of cellular differentiation, including connexin 43, and apoptosis increased in the intervention arm. Clearly this trial is too small in size to draw any real conclusions, however, it certainly adds fuel to the fire of debate. However, given the paucity of knowledge of the phamacokinetic properties of lycopene, of the potential risks of excess dietary intake and any hard scientific evidence as to its benefits, it is premature to recommend pharmacological supplementation of lycopene. Any dietary recommendations, therefore, should be based on those from the organizations listed above that emphasize the general benefits of diets high in a whole variety of vegetables and fruits, including tomatoes and tomato-based products. |
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| References |
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