Lycopene | Cam-Cancer

Lycopene

Abstract and key points

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.

For the treatment of prostate cancer, clinical evidence is available from one systematic review (SR) and one additional randomized controlled trial (RCT); for the prevention of prostate cancer, clinical evidence is available from two SRs and one additional RCT for prevention. There are also three RCTs for oral submucous fibrosis and one for cisplatin-induced nephrotoxicity.

Anticancer treatment

  • Prostate specific antigen (PSA) levels: There is insufficient high-quality evidence for lycopene as a cancer treatment from one systematic review and one good-quality RCT assessing PSA levels.

Supportive care

  • Cisplatin-induced nephrotoxicity: Lycopene may decrease complications due to cisplatin-induced nephrotoxicity but evidence from one RCT is very limited.

Cancer prevention

  • Prostate cancer: There is insufficient evidence to support the recommendation of lycopene for prostate cancer prevention based on two SRs and one additional RCT.

  • Oral submucous fibrosis: Three RCTs provide some evidence for lycopene reducing the symptoms of oral submucous fibrosis but the trials are small and of poor quality.

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

Document history

Fully updated and revised in October 2020 by Ava Lorenc
Fully updated and revised in September 2018 by Ava Lorenc
Summary first published in July 2013, authored by Gabriele Dennert.

Citation

Ava Lorenc, Gabriele Dennert, CAM Cancer Consortium. Lycopene [online document], http://cam-cancer.org/en/lycopene. November 9th, 2020.

What is it?

Description

Lycopene forms the red pigment in fruit such as tomatoes, apricots, guavas, pink grapefruits, rosehips or watermelons (Diener 2008) 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. Lycopene was named after the fruit from which it was first isolated, namely the tomato (Lycopersicum esculentum), by the chemist C.A. Schunck in 1903 (Schunck 1904).

In Western countries, tomatoes and tomato products have been found to be the major nutritional source of lycopene for humans. Lycopene supplements or lycopene-enriched functional foods are marketed by various companies. In a US sample of prostate cancer patients, 11% of men used lycopene or tomato products (Wang 2016). Intake in the general population has been estimated at 4·1mg/d in Belgium (Vandevijvere 2013) and 3.1 mg/d in Spain (Esèvez- Santiago 2016) .

Ingredient and quality issues

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 per100g (Rao 2007). For safe use of tomato leaf extract the authors of an animal study recommend lower doses (250 and 500 mg/kg) for prolonged use (Nguenang 2020).

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 Diener 2008). 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 Basu 2007). 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 days (Ross 2011). 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 dispersion (Li 2017, Jain 2018, Faisal 2013). Lycopene seems to be eliminated and excreted via the bile duct and the kidneys.

Alleged indications

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 chemotherapy (Sahin 2010).

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) (Catano 2018, Chen 2015, Rowles 2017, Wang 2015, Giovannucci 1999) as well as cardiovascular diseases (Cheng 2017). Lycopene has therefore been promoted for cancer prevention and general health improvement.

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 cancer (Yang 2013), and lycopene intake is marginally associated with reduced risk of pancreatic cancer (Chen 2016), but lycopene intake is not significantly associated with the risk of ovarian cancer (Li 2014), colorectal cancer (Wang 2016), colon cancer (Slattery 2000), or non-Hodgkin lymphoma (Chen 2016) . Individual studies are also contradictory: for lung cancer (Michaud 2000), 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 risk (Eliassen 2015) but a previous 9.9 year follow up study found no protective association (Sesso 2005).

Mechanisms of action

Several biological mechanisms of lycopene and its metabolites have been described and suggested as linked to cancer development and prevention in humans (Mein 2008), including: growth inhibition and induction of apoptosis G0/G1 cell cycle arrest (Rotelli 2015), inhibition of MMP-7 expression and leptin-mediated cell invasion (Rotelli 2015), decreased genomic instability in low grade prostate cancer, suggesting inhibition of disease progression early on (Nordstrom 2015), and decreased tumour angiogenesis (Zu 2014). 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 effect (Basu 2007). A systematic review concludes that lycopene supplementation significantly decreases the DNA tail length, but does not significantly prolong the lag time of low-density lipoprotein (Chen 2013). 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 seen (van- Breemen 2011) . Llanos et al (Llanos 2014) 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 concentrations (Vrieling 2007) , 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-metabolism (Ford 2012).

Some animal and in-vitro studies found a protective effect of lycopene against smoke carcinogen-induced injury (Aizawa 2016, Mustra 2019) and carcinogenic effects on skin of UVB (Zhou 2019), cutaneous squamous cell carcinoma (via autophagy)(Bi 2019) and chemotherapy/radiotherapy-induced toxicities such as cardiotoxicity, neuropathy, kidney and ovarian injury (Lopez- Jornet 2016, Acar 2014, Kulhan 2019, Stokiljkovic 2019, Zhu 2019, Celik 2020), e.g. nephron- and cardiotoxicity of cisplatin or adriamycin, while others did not (Anjos Ferreira 2007, overview in Sahin 2010). Mice/rat studies found that lycopene reduces hepatic tumours, through inhibiting NF-kappaB and mTOR pathways and reducing hepatic proinflammatory signalling and inflammatory foci (Sahin 2014, Ip 2013, Ip 2014, Xia 2018).  An SR found evidence to support the biological plausibility that lycopene interacts with the androgen axis in prostate cancer (Applegate 2019) and an in-vitro study found tomato products increase apoptosis in prostate cancer cells (Soares 2019). Lycopene has been shown to reduce gene expression  in gastric cancer cells in-vitro (Han 2019, Kim 2019), in pancreatic cancer in-vitro (Jeong 2019), in cutaneous tumors (Wang 2020), in ovarian cancer in vitro (Xu 2019) and in prostate cancer in TRAMP mice (Wan 2014). Other mechanisms identified in animal studies include antioxidant and anti-inflammatory mechanisms (ovarian cancer and prostate cancer)(Jiang 2018) (Sahin 2018) , reduction of growth factors (Tjahjodjati 2020) and antioxidant defence (cutaneum carcinoma) (Shen 2014). An in-vitro study found that LYC-oxidation derivatives or metabolites in lycopene are involved in growth inhibition of breast cancer cells (Arathi 2018).

In-vitro studies found that lycopene may enhance the effects of treatment of lung cancer (Jiang 2019) and melanoma (Zhu 2019)

In an in-vitro model, lycopene at a physiological level did not show a significant effect on the proliferation of normal and malignant cells (Burgess 2008), and two animal studies found that lycopene did not reduce carcinogenesis in TRAMP mice (Rowles 2020) (Conlon 2015). 

Legal issues

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

Costs 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?

For prostate cancer clinical evidence is available from one systematic review (SR) and one additional randomized controlled trial (RCT) for treatment as well as two SRs and one additional RCT for prevention. There are also three RCTs for oral submucous fibrosis and one for cisplatin-induced nephrotoxicity.

Anticancer treatment

  • Prostate specific antigen (PSA) levels: There is insufficient high-quality evidence for lycopene as a cancer treatment from one systematic review and one good-quality RCT assessing PSA levels.

Cancer prevention

  • Prostate cancer: There is insufficient evidence to support the recommendation of lycopene for prostate cancer prevention based on two SRs and one additional RCT.
  • Oral submucous fibrosis: Three RCTs provide some evidence for lycopene reducing the symptoms of oral submucous fibrosis but the trials are small and of poor quality.

Supportive care

  • Cisplatin-induced nephrotoxicity: Lycopene may decrease complications due to cisplatin-induced nephrotoxicity but evidence from one RCT is very limited.

Description of included studies

Anticancer treatment

Haseen and colleagues (2009) identified eight intervention studies for their systematic review of lycopene supplementation in men with prostate cancer (Haseen 2009). Two of them were RCTs (Ansari 2003, Kucuk 2001). One was a non-randomized clinical trial (Kim 2003) and five were uncontrolled intervention studies (Ansari 2004, Barber 2006, Chen 2001, Jatoi 2007, Clark 2006).
All studies reported on changes of PSA level as the surrogate parameter for prostate cancer progression. Only one RCT (Ansari 2003) 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’ (Haseen 2009). In summary, reviewers concluded that there is not sufficient evidence to recommend the use of lycopene supplements in routine care for prostate cancer patients.

Since the systematic review, one RCT on PSA levels (Paur 2016) has been published. Paur et al (Paur 2016) 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.

Cancer prevention

In addition to the epidemiologic evidence described above (see ‘Claims of efficacy’), two systematic reviews of RCTs of lycopene for prostate cancer prevention (Llanos 2014, Cui 2017) and three RCTs for the precancerous condition oral submucous fibrosis (OSMF) (Saran 2018, Karemore 2012,  Beenakumary 2019) are included in this summary.

Prostate cancer

Two systematic reviews and one subsequently published RCT (Beynon 2018) 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” (Ilic 2011). The review identified three RCTs investigating lycopene for prostate cancer prevention (Mohanty 2005, Bunker 2007, Schwarz 2008). Two RCTs used prostate specific antigen (PSA) levels as surrogate parameters for prostate cancer development but only one study (Mohanty 2005) 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 significantly (Cui 2017). Beynon et al (Beynon 2018) subsequently conducted a high quality, powered RCT of 128 men with raised PSA levels comparing tomato products, tomato products plus supplements and standard care. They found no differences in PSA except for subgroup analysis of intermediate risk prostate cancer patients.

Oral submucous fibrosis

Three  RCTs have tested lycopene supplementation for oral submucous fibrosis (OSMF), a potentially malignant disorder (Saran 2018, Karemore 2012)(Beenakumary 2019). Beenakumary et al (Beenakumary 2019) randomised 60 patients with OSMF to lycopene supplement, lycopene supplement + dexamethasone or dexamethasone + hyaluronidase.  They found that lycopene was not as effective as dexamethasone + hyaluronidase.  Saran et al (Saran 2018) 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 Motwani (Karemore 2012) 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 all three studies may be subject to detection bias and underpowered samples.

Supportive care

Nephrotoxic side effects of cancer treatment

Mahmoodnia et al 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. (Mahmoodnia 2017)  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 and the authors recommend additional studies using other nephrotoxicity outcomes.

Is it safe?

Supranutritional intake (10 mg/day) of lycopene seems to be generally safe in men and non-pregnant women (Norwegian Scientific Committee for Food Safety).

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 men (Haseen 2009). 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’ (Shao 2008).

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 placebo (Banerjee 2009).

Datta et al (Datta 2013) 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.  An animal study found that high doses of tomato leaf extract (1000mg/kg) increased urea levels and total serum proteins (Nguenang 2020).

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 combination (Veeramachaneni 2008) However, the relevance of this finding for humans is unclear.

One recent in-vitro study (Sunaga 2012) 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 content (Feifer 2002).

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 contains (Linus Pauling Institute).

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