This section contains the following key information:
- Lycopene is a carotenoid, a natural pigment made by plants and various fruits and vegetables, including tomatoes, apricots, guavas, and watermelon.
- Lycopene's absorption is improved with concurrent dietary fat intake.
- Lycopene inhibits androgen receptor expression in prostate cancer cells in vitro and, along with some of its metabolites, reduces prostate cancer cell proliferation and may modulate cell-cycle progression.
- Lycopene may also affect the insulin-like growth factor (IGF) intracellular pathway in prostate cancer cells.
- Results from several in vitro and animal studies have indicated that lycopene may have chemopreventive effects for cancers of the prostate, skin, breast, lung, and liver; however, human trials have been inconsistent in their findings.
- Clinical trials utilizing lycopene in prostate cancer patients with various different clinical presentations (e.g., early stage, prostate-specific antigen (PSA) relapse, advanced disease) have yielded inconsistent results.
- The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS). In clinical trials involving prostate cancer patients, doses ranging from 10 to 120 mg/d have been well tolerated, with only occasional mild-to-moderate gastrointestinal toxicities.
Lycopene is a carotenoid, a natural pigment made by plants, which helps to protect plants from stress, and it also transfers light energy during photosynthesis. Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products. The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than it is in raw tomatoes. When ingested, lycopene is broken down into a number of metabolites and is thought to have various biological functions, including antioxidant capabilities and a role in gap-junction communication.
There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing. Results of a randomized study published in 2005 revealed that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil. According to one study, there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this same study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.
Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease, although some interventional studies have shown mixed results. Lycopene may protect against cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins. A number of in vitro and in vivo studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver. However, epidemiological studies reported to date have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. The few human intervention trials have been small and generally focused on intermediate endpoints and thus have not been definitive.[2,10]
In 2004, the FDA received two petitions for qualified health claims regarding tomatoes, lycopene, and reduced cancer risk. In a 2007 review, the FDA concluded there was not enough evidence to support a claim that lycopene helps reduce cancer risk. The FDA found there was no evidence of a link between tomato consumption and lung, colorectal, breast, cervical, or endometrial cancers, and there was limited evidence for an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.Preclinical/Animal Studies
In vitro studies
Many in vitro studies have been conducted examining a link between lycopene and prostate cancer.
Treating normal human prostate epithelial cells with lycopene resulted in dose-dependent growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene may lower the risk of prostate cancer.
In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12’-lycopenal, a lycopene metabolite, also reduced prostate cancer cell proliferation and may also modulate cell-cycle progression.
Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), total cholesterol, and cell growth, and an increase in apoptosis. However, adding mevalonate prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anticancer activity of lycopene. Lycopene may also affect cholesterol levels in prostate cancer cells by activating the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ATP-binding cassette, subfamily 1 (ABCA1) pathway, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and differentiation of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ antagonist, cell proliferation increased while treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.
Adding lycopene to medium containing the LNCaP human prostate adenocarcinoma cell line resulted in decreased DNA synthesis and inhibition of androgen-receptor gene-element activity and expression. In a study that examined the physiologically relevant concentration of lycopene (2 mmol/L) or placebo for 48 hours on protein expression in human primary prostatic epithelial cells, proteins that were significantly upregulated or downregulated following lycopene exposure were those proteins involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the AKT /mTOR cascade. These data are consistent with previous studies, suggesting that lycopene can prevent malignant transformation in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression.
Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and docetaxel, a drug used to treat patients with castration -resistant prostate cancer, or each drug alone. The combination treatment inhibited proliferation in four of five cell lines to a greater extent than did treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the IGF-1 receptor (IGF-1R) pathway.Animal studies
In a chemoprevention study, 59 transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared with control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.
Ketosamines are carbohydrate derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea (NMU)/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.
Lycopene has also been studied for potential therapeutic effects in xenograft studies. In one study, athymic nude mice were injected with human androgen-independent prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or beta-carotene (16 mg/kg body weight). Supplementing mice with lycopene or beta carotene resulted in decreased tumor growth. In an in vitro study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines. In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg per day) administered via gavage, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.Human Studies
Several epidemiologic studies have assessed potential associations between lycopene intake and prostate cancer incidence.
Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risks of prostate cancer.[11-16] Prospective and case control studies have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[11,18-21] while other studies have failed to demonstrate such a connection.
An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study in Finland. In this prospective cohort study, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio, 0.55; 95% confidence interval (CI), 0.34–0.89; P = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (risk ratio, 0.43; 95% CI, 0.23–0.79; P = .007) but not prostate cancer.
A 2004 meta-analysis of studies investigating tomato intake and prostate cancer risk found a small positive effect of tomato products on risk reduction. Among men who consumed high amounts of raw tomato products, the relative risk (RR) of prostate cancer was 0.89 (95% CI, 0.80–1.00), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomato products, the RR was 0.81 (95% CI, 0.71–0.92). A 2013 meta-analysis, including four of five cohort studies from the 2004 meta-analysis, two new meta-analyses and three case-control studies from the previous study plus eight new ones, reported less convincing evidence for risk reduction. Among men who consumed high amounts of raw tomato products, the RR of prostate cancer was 0.81 (95% CI, 0.59–1.10), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomatoes products, the RR was 0.85 (95% CI, 0.69–1.06). These authors concluded that tomato may play a modest role in the prevention of prostate cancer.
The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is an ongoing, prospective study that has been a source of subjects for investigations of an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed up for an average of 4.2 years. Lycopene and tomato product intakes were assessed via Food Frequency Questionnaires. Overall, no association was found between dietary intake of lycopene or tomato products and the risk of prostate cancer. However, among men with a family history of prostate cancer, increased lycopene consumption was associated with decreased prostate cancer risk. A follow-up study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggest that there was no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.
The Health Professionals Follow-up Study obtained dietary information and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Higher lycopene intake was inversely associated with total prostate cancer risk (hazard ratio [HR], 0.91; 95% CI, 0.84–1.00) and lethal prostate cancer risk (HR, 0.72; 95% CI, 0.56–0.94). A subset analysis was restricted to men who had at least one negative PSA test at the onset, to reduce the influence of PSA screening on the association. The inverse association became markedly stronger (HR, 0.47; 95% CI, 0.29–0.75 for lethal prostate cancer). Levels of tumor markers for angiogenesis, apoptosis, and cellular proliferation and differentiation were monitored. Three of the tumor angiogenesis markers were strongly associated with lycopene intake, so that men with higher intake had tumors that demonstrated less angiogenic potential.
The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Given these caveats, results based on epidemiological evidence should be interpreted with caution.Intervention studies
A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.
Healthy males participated in a crossover design study that attempted to differentiate the effects of tomatoes from those of lycopene. After study entry, the participants consumed their usual diet for 1 week followed by a 2-week washout period on a lycopene-free diet. Next, they were randomly assigned to consume either yellow tomato paste (0 mg/day lycopene) (Group 1) or red tomato paste (16 mg/day lycopene) (Group 2) for 1 week as part of their regular diets, followed by a second 2-week washout period. Then, the participants in Group 1 crossed over to red tomato paste, and the participants in Group 2 crossed over to yellow tomato paste for 1 week as part of their regular diets, followed by a third 2-week washout period. Finally, the participants in Group 1 took a capsule of lycopene (16 mg/day) and the participants in Group 2 took a placebo daily for 1 week. Circulating lycopene levels increased only after consumption of red tomato paste and the lycopene capsules. Changes in serum PSA level, antioxidant status, and IGF-1 level were not modified by the consumption of tomato paste and lycopene. When prostate cancer cells were treated in vitro with sera collected from participants after red tomato paste consumption, IGF binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up regulated, and cyclin-D1, p53, and Nrf-2 were down regulated compared with expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after yellow tomato paste consumption. These findings suggest that lycopene may not be the only factor responsible for the protective effects of tomatoes.
In another study, the effect of tomato sauce on apoptosis in benign prostate hyperplasia (BPH) tissue and carcinomas was examined. Patients who were scheduled for prostatectomy were given tomato sauce pasta entrees (30 mg/day of lycopene) to eat daily for 3 weeks before surgery. Patients scheduled for surgery who did not receive the tomato sauce pasta entrees served as control subjects. Those who consumed the tomato sauce pasta entrees exhibited significantly decreased serum PSA levels and increased apoptotic cell death in BPH tissue and carcinomas.
In a third study, patients with high-grade prostate intraepithelial neoplasia (HGPIN) received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in those treated with lycopene supplements, compared with those who did not take the supplementation. During follow-up, adenocarcinomas were diagnosed more often in patients who had not received the supplements than in patients who had received lycopene (6/20 vs. 2/20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer. In another study, men at high risk of prostate cancer (e.g., HGPIN) were randomly assigned to receive a daily multivitamin (that did not contain lycopene) or the same multivitamin and a lycopene supplement (30 mg/day) for 4 months. No statistically-significant difference was observed in serum PSA levels between the two treatment groups. These findings suggest that, although lycopene supplements may be safe to take for at least 4 months, they may not affect PSA levels.
In another study, 32 men with HGPIN received a lycopene-enriched diet (20–25 mg/day lycopene from triple-concentrated tomato paste) before undergoing a repeat biopsy after 6 months. No overall clinical benefit was seen in decreasing the rate of progression to prostate cancer. Baseline PSA levels showed no significant change. Prostatic lycopene concentration was the only difference between those whose repeat biopsy showed HGPIN, prostatitis, or prostate cancer. Prostatic lycopene concentration below 1 ng/mg was associated with prostate cancer at the 6-month follow-up biopsy (P = .003).
Other studies have examined the potential therapeutic effect of lycopene-containing products in patients with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in patients with localized prostate cancer in a 2002 pilot study. Patients received lycopene supplements (30mg/day) or no intervention twice daily for 3 weeks prior to radical prostatectomy. Patients who received the lycopene supplements had smaller tumors and lower serum PSA levels than patients who did not receive the supplements. These results suggest that lycopene may be beneficial in prostate cancer treatment. A 2006 study investigated whether lycopene supplements (10 mg/day) would affect PSA velocity in patients with localized prostate cancer over the course of 1 year of treatment. There was a statistically significant decrease in PSA velocity following lycopene treatment as well as a large, but not statistically significant, increase in PSA doubling time.
In a phase II, randomized, placebo-controlled trial, 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene or no supplement from time of biopsy to prostatectomy (30 days). Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm. No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, similar to levels observed in previous studies in men with prostate cancer. At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and a significant increase in mean plasma estradiol was observed (24.90 [+/−7.94] to 32.30 [+/−7.93]; P = .02). In addition, significant increase in serum sex hormone-binding globulin (SHBG) (39.31 [+/−16.04] to 45.67 [+/−19.83]; P = .022) and total estradiol (27.54 pmol/L [SD 7.82] to 37.64 pmol/L [SD12.65]; P = .006) was observed in the 45 mg/day lycopene-supplemented arm, with no significant change in serum testosterone. However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki-67, compared with the control group. Notably, 75% of subjects in the 30 mg lycopene-supplemented arm had a decrease in the percentage of cells expressing Ki-67, compared with the subjects in the control group, where 100% of the subjects observed an increase. These changes were not statistically significant, compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.
In one study, prostate cancer patients (N = 36) who had biochemical relapse following radiation therapy or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/day). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.
In a 2004 open-label study, patients with hormone-refractory prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/day of lycopene) for 3 months. Of the study's participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient (5% of the total sample) exhibited a complete response after treatment. In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/day) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a control group, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.
In another study, 46 patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/day) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level, suggesting that lycopene may not be effective therapy for patients with androgen-independent prostate cancer. A number of participants experienced gastrointestinal side effects after eating the tomato paste or drinking the tomato juice.
In one 2011 study that explored the effects of lycopene and fish oil supplements on gene expression, men with low-risk prostate cancer were randomly assigned to receive lycopene (30 mg of lycopene/day), fish oil (3 g of fish oil capsules/day), or a placebo daily for 90 days. Gene expression analysis showed no statistically significant differential expression of individual genes associated with the consumption of fish oil or lycopene supplements. However, pathway analysis revealed that an oxidative stress response pathway was significantly modulated following lycopene or fish oil supplement use compared with placebo (fish oil: P = .01, lycopene: P = .001).Current Clinical Trials
Check NCI’s list of cancer clinical trials for CAM clinical trials on lycopene for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.Adverse Effects
Lycopene has been well tolerated in a number of clinical trials involving prostate cancer patients.[30,32,33,36,39] When adverse effects occurred, they tended to present as gastrointestinal symptoms and, in one study, the symptoms resolved when lycopene was taken with meals. Another study reported that one participant withdrew because of diarrhea.
The FDA has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS).References
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