Lycopene | Cam-Cancer

Lycopene

Abstract and key points
  • Lycopene is a carotenoid and forms the red pigment in fruit, such as tomatoes or apricots.
  • Two systematic reviews summarize the clinical evidence for prostate cancer prevention and two RCTs studied lycopene for oral submucous fibrosis (a precancerous condition)
  • A systematic review summarizes the evidence for prostate cancer treatment, and two subsequent RCTs studied tomato products or lycopene for prostate cancer or the side effects of cancer treatment.
  • Evidence is insufficient to recommend or discourage additional intake of lycopene for cancer prevention or treatment.
  • In men, lycopene seems to be generally safe.

Lycopene is a carotenoid that forms the red pigment in fruit, such as tomatoes or apricots.

Lycopene has been suggested to exhibit antioxidant activities, inhibit cell proliferation and induct apoptosis, thus protecting against cancer (in particular prostate cancer) and providing health benefits for cancer patients. The additional intake of processed tomato products (juice), functional foods enriched with lycopene, or nutritional supplements is marketed based on such claims. This summary concerns the supranutritional intake (i.e. in addition to the content of the daily diet) of lycopene in the form of supplements or functional foods.

Systematic reviews and meta-analyses of epidemiological studies show some associations between higher intake of lycopene and reduced risk of prostate cancer but have produced contradictory evidence regarding other cancers.

Clinical evidence for prostate cancer is available from three systematic reviews – two for cancer prevention and one for treatment. These reviews concluded that there is insufficient evidence to support the recommendation of lycopene for prostate cancer prevention or treatment. A subsequent good quality randomized controlled trial (RCT) found tomato products did not reduce prostate specific antigen (PSA) compared to control, although it may reduce PSA in intermediate risk prostate cancer patients. Two RCTs provide some evidence for lycopene reducing the symptoms of oral submucous fibrosis but the trials are of poor quality. Lycopene may decrease complications due to cisplatin-induced nephrotoxicity but evidence from one RCT is very limited.

In men, the ingestion of lycopene seems to be generally safe.

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Document history

Fully updated and revised in September 2018 by Ava Lorenc
Summary first published in July 2013, authored by Gabriele Dennert.

Citation

Gabriele Dennert, CAM-Cancer Consortium. Lycopene [online document]. September 14, 2018.

What is it?

Description

Lycopene forms the red pigment in fruit such as tomatoes, apricots, guavas, pink grapefruits, rosehips or watermelons1. and is involved in the photosynthesis of plants, algae and other organisms that actively generate energy through photosynthesis. It is chemically a carotenoid, but is not an essential food ingredient for humans.

In Western countries, tomatoes and tomato products have been found to be the major nutritional source of lycopene for humans.

Ingredient(s)/Components

Lycopene is a lipophilic, acyclic (C40H56) carotenoid with no provitamin-A activity, which means it is not metabolized to vitamin A in the body. It is insoluble in water and exists naturally in an all-trans isoform and several cis-isoforms.

Application and dosage

The level of intake optimal for human health has not been established. This summary concerns the supplemental intake of lycopene. Supporters of the supranutritional intake of lycopene often recommend adding between 15 and 40 mg to their daily diet. Lycopene is obtained from processed tomato products (juice), functional foods enriched with lycopene or as nutritional supplements. Nutritional supplements contain pure lycopene, extracted from either natural or synthetic sources, at doses of between 5 and 25mg per tablet or capsule.

Tomato juice or sauce contains about 9mg of lycopene per100g2.

Lycopene is intestinally absorbed. Some studies found that absorption is higher in the presence of dietary lipids, and from processed tomato products, than from raw tomatoes. (Overview in 1) Several studies have shown that the additional intake of lycopene (between 20 and 40mg/day) in the form of tomato products or nutritional supplements increased the plasma lycopene level. (Overview in 3) One pharmacokinetic study found peak plasma levels of lycopene at 0.5–6 hours after oral ingestion and an elimination half-life of between two and five days. Lycopene and its metabolites were transported to the skin in this study, where it remained detectable for up to 42 days4. Various novel delivery systems have been shown in animal studies to improve bioavailability, e.g. green tea catechin derivatives, protein nanoparticles or lipid based solid dispersion5-7. Lycopene seems to be eliminated and excreted via the bile duct and the kidneys.

History/provider(s)

Lycopene was named after the fruit from which it was first isolated, namely the tomato (Lycopersicum esculentum), by the chemist C.A. Schunck in 19038.

Lycopene supplements or lycopene-enriched functional foods are marketed by various companies.

Claims of efficacy

Systematic reviews of epidemiologic studies show that higher intake of lycopene is associated with a reduced risk of developing prostate cancer (although not advanced prostate cancer)9-13 as well as cardiovascular diseases14. Lycopene has therefore been promoted for cancer prevention and general health improvement. It has been suggested that it exhibits antioxidant activities, reduces tumour angiogenesis, inhibits cell proliferation and inducts apoptosis.

To date, there is contradictory epidemiologic evidence regarding the association of lycopene intake and the risk of other cancers: meta-analyses showed consumption of large amounts of tomato products is associated with a reduced risk of gastric cancer15, and lycopene intake is marginally associated with reduced risk of pancreatic cancer16, but lycopene intake is not significantly associated with the risk of ovarian cancer17, colorectal cancer18, colon cancer19, or non-Hodgkin lymphoma20. Individual studies are also contradictory: for lung cancer21, Michaud  et al found a reduced risk associated with higher lycopene levels or intake. For breast cancer one 20 year follow up study found a reduced risk22 but a previous 9.9 year follow up study found no protective association23.

Alleged indication(s)

Lycopene has been proposed as being active in the prevention of cancer, in particular prostate cancer, and other disease, e.g. cardiovascular diseases. As well as exhibiting beneficial effects in prostate cancer and lung cancer patients, it has been suggested as helpful in protecting against the adverse effects of chemotherapy24.

Mechanism(s) of action

Several biological mechanisms of lycopene and its metabolites have been described and suggested as linked to cancer development and prevention in humans25, including: growth inhibition and induction of apoptosis G0/G1 cell cycle arrest26, inhibition of MMP-7 expression and leptin-mediated cell invasion26, decreased genomic instability in low grade prostate cancer, suggesting inhibition of disease progression early on27, and decreased tumour angiogenesis28. However, much of this data s from in vitro studies, and the metabolism and biological effects of lycopene are still not fully understood as, to date, studies have yielded discrepant results.

Some studies with healthy volunteers found that the intake of additional lycopene decreased the level of biomarkers of oxidative stress, while other investigations showed no effect3. A systematic review concludes that lycopene supplementation significantly decreases the DNA tail length, but does not significantly prolong the lag time of low-density lipoprotein29. In one randomized clinical trial (RCT) involving male African American urology patients, no antioxidant effect of lycopene supplementation prior to prostate biopsy (30 mg/day for 21 days) could be seen30. Llanos et al (31) conducted a crossover trial of 70 women at risk of breast cancer who were put on a tomato-based diet (>25 mg lycopene daily) for 10 weeks, compared to a soy-based diet. They found that the tomato-based diet may beneficially increase serum adiponectin concentrations. Another investigation with healthy volunteers suggested that the intake of lycopene (30 mg/day) increased serum insulin-like growth factor (ILGF)-binding protein-1 and -2 concentrations32, which might lower ILGF-levels and prevent its possible cancer-promoting effects. Lycopene has also been linked to androgen metabolism and has been found to lower testosterone levels in mice mediated by genetic variations of enzymes of the carotenoid-metabolism33.

Some animal and in-vitro studies found a protective effect of lycopene against smoke carcinogen-induced injury34 and chemotherapy/radiotherapy-induced toxicities35,36, e.g. nephron- and cardiotoxicity of cisplatin or Adriamycin, while others did not (37, overview in 24). Mice/rat studies found that lycopene reduces hepatic tumours, through inhibiting NF-kappaB and mTOR pathways and reducing hepatic proinflammatory signalling and inflammatory foci38-40. Both lycopene and tomato-based diets reduced gene expression in prostate cancer in TRAMP mice41. Other mechanisms identified in animal studies include antioxidant and anti-inflammatory mechanisms (ovarian cancer)42 and antioxidant defence (cutaneum carcinoma)43.

In an in-vitro model, lycopene at a physiological level did not show a significant effect on the proliferation of normal and malignant cells44and another study found a low-lycopene intervention did not reduce carcinogenesis in mice45.

Prevalence of use

In a US sample of prostate cancer patients, 11% of men used lycopene or tomato products18Intake in the general population has been estimated at 4·1mg/d in Belgium46 and 3.1 mg/d in Spain47.

Legal issues

For functional foods and nutritional supplements, EU and national regulations apply.

Cost(s) and expenditures

Thirty tablets (15–25 mg lycopene each) – one-month’s supply – are available in Europe for around €25 via internet sellers.

Does it work?

Cancer prevention

In addition to the epidemiologic evidence described above (see ‘Claims of efficacy’), two systematic reviews of RCTs of lycopene for prostate cancer prevention31,48 and two RCTs for the precancerous condition oral submucous fibrosis (OSMF) are included in this summary.

Systematic review

Two systematic reviews have looked at lycopene for prostate cancer prevention. A Cochrane systematic review (2011) concluded that ‘there is insufficient evidence to either support, or refute, the use of lycopene for the prevention of prostate cancer”49. The review identified three RCTs investigating lycopene for prostate cancer prevention50-52. Two RCTs used prostate specific antigen (PSA) levels as surrogate parameters for prostate cancer development but only one study50 assessed the incidence of prostate cancer. The latter RCT reported a lower rate of prostate cancer (10% in the lycopene group versus 30% in the comparison group) but was very small (40 participants) and considered to be of unclear risk of bias by the review authors. A larger systematic review (n=13) with meta-analysis published in 2017 of high-grade prostatic intraepithelial neoplasia (precursor or premalignant form of prostate cancer) concluded that lycopene decreased the risk of prostate cancer but not significantly48.

RCTs

Two RCTs have tested lycopene supplementation for oral submucous fibrosis (OSMF), a potentially malignant disorder53,54. Saran et al53 randomised 60 patients to receive 4 mg of lycopene or 300 mg of curcumin thrice daily for 3 months. Lycopene showed better results than curcumin in improving mouth opening; both the drugs were equally effective in decreasing burning sensation in OSMF patients. Lycopene significantly reduced the signs and symptoms of OSMF. Karemore and Motwani54 randomised 92 patients to either 4mg of Lycopene or placebo tablet twice a day. Lycopene was found significantly efficacious reducing the signs and symptoms of OSMF. However both studies may be subject to detection bias and underpowered samples.

Treatment of cancer patients

Systematic reviews

Haseen and colleagues (2009) identified eight intervention studies for their systematic review of lycopene supplementation in men with prostate cancer55. Two of them were RCTs56,57, one was a non-randomized clinical trial58 and five were uncontrolled intervention studies59-63.
All studies reported on changes of PSA level as the surrogate parameter for prostate cancer progression. Only one RCT56 investigated clinical outcomes: 54 men with metastasized prostate cancer were randomized to orchidectomy or orchidectomy plus lycopene (4 mg/day). After two years, clinical response of bone metastases (as measured in bone scan) and overall survival were higher in the lycopene plus orchiectomy group, suggesting a beneficial effect of lycopene. However, due to shortcomings in methods and reporting of this trial, these findings need to be replicated in larger RCTs before any generalized recommendations for men with advanced prostate cancer can been made. Moreover, as stated by the reviewers, ‘orchidectomy is now rarely performed in Western countries as a prostate cancer treatment and it is unclear whether the results of this study can be generalized to patients receiving medical castration therapy’55. In summary, reviewers concluded that there is not sufficient evidence to recommend the use of lycopene supplements in routine care for prostate cancer patients.

RCTs

Since the systematic review, two RCTs have been published, one on PSA levels64, one on the use of lycopene for nephrotoxic side effects of cancer treatment65.

Paur et al64 randomised 79 patients with prostate cancer to either tomato products containing 30mg lycopene per day, tomato products plus other supplements, or control diet for 3 weeks.  They found no difference in PSA levels between groups in the overall sample, but sub-analysis suggests tomato products may reduce PSA levels in intermediate risk prostate cancer patients. This was a high-quality study, although patients were not blinded.

Mahmoodnia et al65 randomised 120 patients with cancer (candidates for cisplatin-based chemotherapies) to either 25mg lycopene each 12 hours from 24 hours before to 72 hours after cisplatin administration or standard care. They found lycopene decreased the complications due to cisplatin-induced nephrotoxicity through affecting some markers of renal function but not all. The study was double-blind and adequately randomised but lacks information on the sample and follow up.

Is it safe?

Supranutritional intake (10 mg/day) of lycopene seems to be generally safe in men and non-pregnant women66.

Adverse events

Authors of a systematic review of lycopene for prostate cancer patients found no indication that the use of lycopene was harmful in these men55. Also Shao and Hathcock claimed that the ‘absence of any pattern of adverse effects related to lycopene consumption in any of the published human trials provides support for a high level of confidence in the safety of this substance’67.

One RCT in pregnant women indicated a higher rate of adverse effects (preterm labour, low birth weight) in the lycopene group (2mg/day) as compared to placebo68.

Datta et al69 evaluated the tolerance and acceptance of three different amounts (4, 8, or 12 oz) of tomato juice during radiotherapy in 20 men with localized prostate cancer and found it was well tolerated with no gastrointestinal side effects.

Contraindications

There are no known contraindications.

Interactions

One animal study reported a possible interaction between lycopene and alcohol intake, with the enzyme cytochrome P450 2E1 being induced by this combination70. However, the relevance of this finding for humans is unclear.

One recent in-vitro study71 35 found that tomato products, but not lycopene alone, had an inhibitory effect on cytochrome P450 3A4 (CYP3A4)-mediated metabolism, the magnitude of which differed between substrates. As CYP3A4 is involved in the metabolization of multiple drugs, including antibiotics, cytostatic and psychotropic drugs, these findings support caution when large quantities of tomato products are concomitantly taken with CYP3A4-dependent drugs.

Warnings

The actual content of lycopene in commercially available nutritional supplements seems to vary and may differ by as much as +/-38–42% from the stated content72.

Other problems or complications

It is possible that the intake of high amounts of lycopene leads to a discoloration of the skin, because of an accumulation of the yellow-orange pigment this carotenoid contains73.

References
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