Role of Lycopene in Prostate Cancer

By Georges Ramalanjaona, MD, DSc, MBA, FACEP

Cancer of the prostate ranks the second most common malignancy in U.S. men, just behind skin cancer. In 2003, there will be 220,900 new cases in the United States, and about 28,900 men will die of this disease, making it the second leading cause of cancer death in men, exceeded only by lung cancer.1

High-profile cases of prostate cancer reported in the media have highlighted the importance of a variety of treatment options, as well as preventive measures, including the role of dietary factors. Consumption of saturated fat, especially animal fat, is associated with an increased risk of prostate cancer. Conversely, this risk seems to decrease with a high level of consumption of fruits and dark green and yellow vegetables.2

Several epidemiological studies have found an inverse association between lycopene consumption (a major carotenoid found in tomatoes, watermelon, guava, apricots, and pink grapefruit) and prostate cancer risk.3,4 This article will review the current scientific evidence linking intake of lycopene with a reduced risk of prostate cancer.

Pharmacokinetics

Lycopene is an acyclic carotenoid and potent antioxidant devoid of provitamin A activity that provides the red color of fruits and vegetables like tomatoes. Lycopene content varies significantly with the degree of ripening and variety of tomato: Red tomatoes contain 50 mg/kg of lycopene compared to 5 mg/kg in the yellow varieties.5 Recent data reveal that watermelon provides on average 40% more lycopene than an equivalent serving of tomatoes.6

Lycopene appears to be relatively heat stable, and is actually more readily available from tomatoes that have been cooked. A number of factors influence the initial release and subsequent absorption of lycopene from the physical matrix of food. Heating tomato-based food prior to ingestion improves its bioavailability by dissociating the protein-carotenoid complex. Lycopene also is fat-soluble, so eating tomato-based foods with some fat will enhance absorption. The dual action of bile salts and pancreatic lipases facilitates the transfer of lipid micelles containing carotenoids into intestinal mucosal cells via passive diffusion. Chilomicrons then carry lycopene from the intestinal mucosa to the blood stream via lymphatics. Lycopene is stored in the liver and adipose tissue. Under favorable conditions, 30% of ingested lycopene can be absorbed, but the existence of a fat malabsorption syndrome may inhibit lycopene uptake.7 The presence and concentration of other carotenoids may likewise limit lycopene absorption.

Although data are limited, it seems clear that lycopene is not uniformly distributed in human tissues: Lycopene is highly concentrated in the adrenals, testes, and prostate.8 Knowledge of the elimination of lycopene is somewhat limited. Furthermore, it is difficult to study the in vivo degradation of lycopene due to the short half-life of intermediate compounds and the very low concentrations of end products.9

Mechanism of Action

Lycopene is the most efficient scavenger of singlet oxygen among the common carotenoids.10 This free radical scavenging property predominates in a lipophilic environment and occurs through both physical and chemical processes; the physical quenching activity of lycopene is primarily responsible and leaves the lycopene intact, in contrast to chemical quenching, which results in the degradation of the carotenoid, known as "bleaching." The number of conjugated double bonds found within lycopene molecules explains its high quenching capacity compared with other carotenoids. Furthermore, lycopene interacts with other reactive oxygen radicals such as hydrogen peroxide and nitrogen dioxide at low oxygen tension.

Recent evidence suggests that lycopene modulates molecular processes related to carcinogenesis, cell differentiation, and proliferation—independent of its role as an antioxidant.11 Lycopene also increases gap-junctional intercellular communication, which suppresses neoplastic transformation in cell culture systems.11

Epidemiological Studies

Several epidemiological studies have reported the inverse association between dietary lycopene intake and prostate cancer. One early prospective trial was conducted in a cohort of 14,000 Seventh-day Adventist men who completed a dietary questionnaire in 1976 and then were followed for development of prostate cancer over six years.12 During this period, 180 histologically confirmed prostatic cancers were found among 14,000 men. Results showed that a high intake of tomato products (more than five times per week) was associated with significantly decreased prostate cancer risk compared to lower consumption (less than one time per week) (relative risk [RR] = 0.57, 95% confidence interval [CI] 0.35-0.93, P = 0.05).

The largest published study was the Health Professionals Follow-up Study in 1986, which assessed the dietary intake of a cohort of 47,895 men initially free of prostate cancer.13 Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992. Between 1986 and 1992, 812 new cases of prostate cancer were detected, including 773 non-stage A1 (using the old Whitmore grading system). High quintile lycopene intake (more than 10 servings per week) reduced the overall risk of prostate cancer by 35% and high-grade cancer by 53%. The researchers also found that consumption of tomato sauce, as opposed to tomato juice, displayed the strongest inverse association with prostate cancer risk (RR = 0.66, 95% CI 0.49-0.90, P = 0.001).

Two other studies have examined the association between serum lycopene levels and risk of prostate cancer.14,15 The first nested case-control study used serum levels from 25,802 subjects in 1974. A 13-year follow-up of serum lycopene levels from men who developed prostate cancer was compared with those of a matched group (n = 103) of control subjects of the same race and age. Results showed a 6.2% lower mean serum lycopene level in subjects developing prostate cancer compared with the control group (RR = 0.50, 95% CI 0.20-1.29). However, this finding did not reach statistical significance.

The other nested case-control study used serum samples from 22,071 healthy men ages 40-84 years who were enrolled in the Physician’s Health Study in 1982. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1,294 age-matched controls. A statistically significant difference in risk was demonstrated between high quintile and low quintile serum lycopene levels (RR = 0.56, 95% CI 0.34-0.91, P = 0.057).

Clinical Trials

There presently exist only a few randomized, controlled clinical trials (RCT) in the literature addressing the role of lycopene in treating prostate cancer.

In one trial, 26 men ages 51-71 years with newly diagnosed, clinically localized (14 T1, 12 T2) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) or no supplementation for three weeks before radical prostatectomy.16 Surgical specimens were evaluated for pathological stage, volume of cancer, extent of intra-epithelial neoplasia, involvement of surgical margins, and prostatic tissue lycopene levels. Measurement of serum lycopene levels, prostate-specific antigen (PSA), and IGF-1 was conducted at baseline and after three weeks. Seventy-three percent of the men in the intervention group vs. 18% in the control group (P = 0.02) had no involvement of surgical margins and/or extra-prostatic tissue with cancer. Only 67% of subjects in the lycopene group compared to 100% in the control group displayed diffuse involvement of the prostate by high-grade prostatic intra-epithelial neoplasia; the difference was statistically significant (P = 0.05). Prostatic lycopene levels were significantly elevated (47% higher) in the intervention group vs. controls (0.53 vs. 0.36 ng/g of tissue, P = 0.02). There was a trend toward a beneficial effect on PSA levels, as the PSA decreased by 18% in the intervention group compared to a decrease of 14% in the control group (P = 0.25).

These results suggest that lycopene supplementation slows the growth of prostate cancer. Interestingly, serum levels of IGF-1 significantly decreased in both groups. This finding may have been associated with the decrease in cell proliferation in the lycopene group; in the control group, the reported decline in IGF-1 may be the result of lifestyle and dietary changes initiated during the trial.

A recent pilot, single-blind RCT was conducted to study the biological and clinical effects of lycopene supplementation in subjects with localized prostatic cancer.17 Twenty-six men with newly diagnosed cancer were randomly assigned to receive either a tomato oleoresin extract with 30 mg of lycopene (n = 15) or no supplementation (n = 11, control group) for three weeks prior to undergoing radical prostatectomy. The investigators used similar biological and clinical parameters to those described in previous trials. Compared to the lycopene group, more subjects in the control group (100% vs. 67%, P = 0.05) had diffuse involvement of the prostate by cancer. Furthermore, the lycopene group displayed less involvement of surgical margins and/or extra-prostatic tissue with cancer compared to the control group (73% vs. 18%, P = 0.05). The authors suggest that lycopene supplementation may have beneficial effects in localized prostatic cancer.

Two clinical trials currently are under way. The first study, sponsored by the National Cancer Institute (NCI), is a Phase I investigation of lycopene for the chemoprevention of prostate cancer. This is a dose-escalating study to determine the presence of dose-limiting toxicity and maximum tolerated dose of dietary lycopene given orally to healthy male subjects. A total of 25 healthy male subjects ages 18-45 years with a baseline serum lycopene level of less than 600 nM will be enrolled.

The second trial, also sponsored by NCI, is a randomized controlled trial comparing the effectiveness of an isoflavone with that of lycopene prior to surgery for the treatment of patients with stage I or II prostate cancer. The primary objective is the measurement of intermediate biomarkers such as indices of cell proliferation and apoptosis. Eligibility criteria include age between 45 and 80 years with histologically confirmed stage I or II prostate cancer, and scheduled prostate surgery within 4-6 weeks of initial biopsy. Patients will be randomized to seven treatment arms: Arms I-III will receive one of three doses of orally administered isoflavones twice daily and a multivitamin once daily; arms IV-VI will receive one of three doses of lycopene orally twice a day and a multivitamin once daily; arm VII will receive only a daily multivitamin. Plans call for a total of 87 patients to be enrolled.

Adverse Effects

No adverse effects have been reported in the published lycopene supplementation trials, and no significant abnormalities were observed in either biological or chemical parameters.

Contraindications and Precautions

There are reports of potential competition between lycopene and other carotenoids, such as beta-carotene, relative to absorption, distribution, and biological functions.18

Lipid malabsorption due to disease processes, surgery, or drug therapy (e.g., olestra, a fat substitute) reduces lycopene absorption and serum lycopene levels.6 Olestra-induced fat malabsorption inhibits lycopene uptake to a greater extent than other carotenoids such as beta-cryptoxanthin and lutein.

The effects of lycopene in pregnant women and pediatric populations are unknown.

Dosage

The lycopene supplements used in the clinical trials presented were in the form of soft-gel capsules containing 15 mg lycopene, 2.5 mg phytoene/phytofluene, and minor carotenoids.

Average dietary intake of lycopene in the United States is 5 mg daily, mostly consumed from tomato products.

Conclusion

Epidemiological data strongly suggest an inverse relationship between lycopene intake and prostate cancer risk.

Preliminary results from randomized controlled trials advocate for lycopene supplementation as a safe and useful adjunct to the standard treatment of prostate cancer. Lycopene significantly reduced the degree of diffuse involvement of the prostate by cancer, arguing for a potential role in chemoprevention. The small sample size of some of these studies precludes a definitive conclusion regarding the preventive or therapeutic benefit of lycopene supplementation for patients with prostate cancer, but results are promising, and the results of further trials are eagerly awaited.

Recommendation

Clinicians certainly should encourage patients to increase consumption of vegetables and fruits, but we also should specifically point out the potential benefits of increased exposure to watermelon and tomato-based foods rich in lycopene to reduce the risk of prostate cancer. Future clinical trials should clarify the effectiveness, and appropriate dose and duration of administration, of lycopene supplementation for the chemoprevention of prostate cancer, and as a complement to conventional care in patients with advanced stages of the disease.

Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Education, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.

References

1. Cancer Facts & Figures 2003. Atlanta, GA: American Cancer Society; 2003. Available at: www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf.

2. Ziegler RG. Vegetables, fruits, and carotenoids and the risk of cancer. Am J Clin Nutr 1991;535:251S-159S.

3. Norrish AE, et al. Prostate cancer and dietary carotenoids. Am J Epidemiol 2000;151:119-123.

4. Michaud DS, et al. Association of plasma carotenoid concentrations and dietary intake of specific carotenoids in sample of two prospective cohort studies. Cancer Epidemiol Biomarkers Prev 1998;7:283-290.

5. Rao AV, et al. Bioavailability and in vivo antioxidant properties of lycopene from tomato products and their possible role in the prevention of cancer. Nutr Cancer 1998;31:199-203.

6. Arnold J. Watermelon packs a powerful lycopene punch. Agricultural Res June; 2002.

7. Koonsvitsky BP, et al. Olestra affects serum concentration of alpha tocopherol and carotenoids, but not vitamin D or vitamin K. J Nutr 1997;127: 1636S-1645S.

8. Stahl W, et al. Cis-trans-isomers of lycopene and beta-carotene human serum and tissues. Arch Biochem Biophys 1992;294:173-177.

9. Clinton SK. Lycopene: Chemistry, biology and implications for human health and disease. Nutr Rev 1998; 56(2 Pt 1):35-51.

10. Barber NJ, et al. Lycopene and prostate cancer. Prostate Cancer Prostatic Dis 2002;5:6-12.

11. Levy J, et al. Lycopene is more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer 1995;24: 257-266.

12. Mills PK, et al. Cohort study of diet, lifestyle, and prostate cancer in Adventist men. Cancer 1989;64: 598-604.

13. Giovannucci EG, et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 2002;94:391-398.

14. Hsing AW, et al. Serologic precautions of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst 1990;82:941-946.

15. Gann PH, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: Results of a prospective analysis. Cancer Res 1999;59:1225-1230.

16. Kucuk O, et al. Phase II randomized clinical trials of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2001;10:861-868.

17. Kucuk O, et al. Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med 2002;227:881-885.

18. Blakely SR, et al. Bioavailability of carotenoids in tomato paste and dried spinach and their interactions with canthaxathin. FASP J 1994;8:192-195.