Lycopene for Prevention and Treatment of Prostate Cancer

Kaia M. Everson, Pharm.D.; Cydney E. McQueen, Pharm.D.

Disclosures

Am J Health Syst Pharm. 2004;61(15) 

Prostate cancer is the most frequent type of cancer in American men. An estimated 189,000 new cases were diagnosed in the United States in 2002, and more than 30,000 men died of the disease. Despite these statistics, most men die "with prostate cancer" as opposed to "of prostate cancer," because the tumor is often relatively slow growing.[2] Even so, prostate cancer can cause significant suffering because of such symptoms as urinary retention and bone pain. The risk of prostate cancer increases rapidly after age 50, and the tumor is especially prevalent in Western populations, particularly African-American men.[3]

Because of the large impact of prostate cancer, there is great interest in new methods of prevention and treatment; some of these appear to reduce mortality.[4] Lycopene is a natural product that has recently gained attention as an agent for prostate cancer prevention and treatment.

Lycopene, a member of the carotenoid pigment family, is common in humans and found in the blood and tissues.[5] Carotenoids include at least 600 pigments, most of which provide bright colors to various plants. Lycopene gives tomatoes and other fruits and vegetables a red color, while serving primarily to protect cells from photosensitization and to aid in photosynthesis.[6] The lycopene molecule contains 40 carbons, and theoretically there are 2048 isomers, although only a few are found in nature.[2] The all-trans form is the most stable in nature and therefore the most common; however, the human body tends to contain more cis isomers. It is not known how the all-trans isomer is converted to the cis isomers; theories include heat, food processing, and conversion in the body.[2,3]

Lycopene is found in high concentrations in tomatoes and tomato products, such as ketchup, tomato paste, and tomato sauce. Over 80% of the lycopene in American diets comes from tomato products. Not all tomatoes have equal amounts of lycopene. Concentrations vary from 50 mg/kg in red tomatoes to 5 mg/kg in yellow tomatoes. Other reddish foods, such as watermelon, papaya, and pink grapefruit, may also contain lycopene, but at lower concentrations than in tomatoes.[2,3,7]

Along with its potential role in preventing and treating prostate cancer, lycopene has been studied for use in general cancer prevention, arthrosclerosis prevention, reduction of asthma symptoms, and immune stimulation.[5,8]

Prostate Cancer Prevention. One of the first investigations to suggest a possible relationship between lycopene use and prostate cancer risk was a case-control study published in the late 1970s. It was reported that high consumers of lycopene, defined as people consuming lycopene in foods more than 14 times per month, had a 30% lower risk of prostate cancer than people with low intake, defined as less than three consumptions per month.[6] However, another case-control study (in Hawaii) did not show an association between lycopene and prostate cancer.[9] The Hawaiian study was limited in that only tomatoes were considered, not tomato products such as sauce and ketchup; also, the actual amounts consumed were not reported.[6,9] Many other studies have been conducted, with variable results.[6]

In light of the mixed results of the case-control studies, prospective studies were initiated, with four completed to date. The first of these involved a cohort of 14,000 Seventh-day Adventists. In this observational study, a higher consumption of tomatoes was associated with a significantly lower risk of prostate cancer. The same study also found a risk reduction with consumption of beans, lentils, and peas, none of which contain lycopene.[6]

The largest study was the Health Professionals Follow-up Study.[6,10] In 1986 a survey of food intake was sent to a large cohort of health care professionals (n = 47,894); follow-up surveys were sent in 1988, 1990, and 1992. The information was analyzed for trends in eating habits and various diseases, and consumption of several carotenoids was evaluated for a possible association with reduced risk of prostate cancer. Only lycopene was associated with a risk reduction (relative risk [RR] = 0.79, 95% confidence interval [CI] = 0.64-0.99). The foods associated with significant risk reduction were tomato sauce, pizza, and strawberries; the risk reduction for uncooked tomatoes was not significant. Tomato sauce and pizza are rich sources of lycopene, whereas strawberries, although red, do not contain lycopene. Tomato juice did not show an association, perhaps, the authors hypothesized, because of its low consumption. The association with strawberries was unexplained.[10] The authors concluded that consumption of tomato-based foods may be linked to a reduced risk of prostate cancer.

Preliminary results of another study also showed a prostate cancer risk reduction in heavy consumers of lycopene-containing products, while one cohort study done in the Netherlands did not observe a risk reduction.[6] The author explained the conflicting results by stating that tomato consumption in the Netherlands is low; also, no distinction was made between cooked and raw tomato products.

Prostate Cancer Treatment. Kucuk et al.[11] explored the effects of lycopene use prior to radical prostatectomy. Twenty-six men with newly diagnosed, localized prostate cancer were randomized to either placebo (n = 11) or a 15-mg capsule of lycopene (n = 15) twice daily with meals for three weeks before surgery. The lycopene supplement used in the study, Lyc-o-mato (LycoRed Natural Products Industries, Ltd., Beer-Sheva, Israel), is derived from whole tomatoes and contains 15 mg of lycopene, as well as the naturally occurring ingredients phytoene, phytofluene, β-carotene, phytosterols, and vitamin E.[12] The authors did not discuss what effects, if any, these other substances may have had. Levels of prostate-specific antigen (PSA) decreased by 18% in the intervention group and increased by 14% in the control group (p = 0.25). Although 80% of the intervention-group patients had tumors of 4 mL or less after treatment, only 45% of patients in the control group had this result; the difference was not significant (p = 0.22). Surgical-margin involvement was found in 4 (27%) of 15 patients in the intervention group and 9 (82%) of 11 control patients (p = 0.02). The study did suggest that 15 mg of lycopene twice daily may modify the disease. There was no significant difference in plasma levels of lycopene, but the mean lycopene level in prostate tissue was 47% higher in the intervention group.[11,13] Whether lycopene alone was responsible for the changes is unknown.[13] Larger studies are needed to determine the ideal dosage.

A recent study examined the use of lycopene after orchiectomy for prostate cancer.[14] Fifty-four men with confirmed prostate cancer were randomized to either orchiectomy (n = 27) or orchiectomy plus 2 mg of lycopene twice daily (n = 27). The lycopene was started the day of the surgery. A serum PSA test, a bone scan, and uroflowmetry were performed at baseline and every three months after orchiectomy. A complete response was defined as a normal PSA concentration (<4 ng/mL). A partial response was defined as a level half of the initial value. Progressive, worsening disease was defined as a 25% increase in the PSA level or negative changes in bone scans. The study was continued for two years. Overall PSA levels decreased in both groups but appeared to decrease more rapidly in the lycopene group. However, the only significant difference between the groups' PSA levels was found at month 24 (p < 0.001). The lycopene group had more complete responders than the group given orchiectomy alone (11 versus 21) (p < 0.05), fewer progressers (7 versus 2) (p < 0.05), and fewer deaths at two years (12 versus 7) (p < 0.001). Although only relatively small studies have looked at the role of lycopene in prostate cancer treatment, there appears to be some benefit.

Some interesting case reports on the use of lycopene for prostate cancer have been published. One described a dramatic decrease in PSA levels.[15] A 62-year-old man diagnosed with prostate cancer in 1989 was started on leuprolide therapy in the early 1990s. The therapy was discontinued in 1996 because the patient was asymptomatic, despite an increase in the PSA concentration from 1 to 29 ng/mL. His cancer was not responsive to antiandrogen or other therapies. The patient entered hospice care in March 1999 with a PSA concentration of 365 ng/mL and began taking lycopene 10 mg daily and saw palmetto 300 mg three times daily. His PSA in April 1999 was 139.6 ng/mL and had further decreased to 8.1 ng/mL in May; it remained between 3.0 and 8.0 ng/mL for the next 18 months. The patient became asymptomatic and remained asymptomatic at the last follow-up before the case report was published. Although the patient was also taking saw palmetto, the authors felt that the dramatic reduction in PSA was probably attributable to lycopene. Studies have suggested that saw palmetto improves the quality of life associated with benign prostatic hyperplasia but has no effect on PSA levels.[16]

Other Uses. Because of the possible role of lycopene in prostate cancer prevention and treatment, as well as lycopene's strong antioxidant effects, researchers are examining lycopene for general cancer prevention. Several large epidemiologic studies have been conducted. Results have been negative for colon cancer and inconclusive for other types of cancer, including breast, cervical, esophageal, laryngeal, ovarian, and pancreatic cancer.[7] An analysis of data from the Health Professionals Follow-up Study and the Nurses' Health Study examined intake of all carotenoids and found that α-carotene and lycopene were associated with a lower risk of lung cancer.[17] A similar Finnish study did not find an impact of lycopene on lung cancer. Before lycopene can be recommended for routine use for lung cancer, many more studies are needed.

One study found a benefit of lycopene for preventing or reducing symptoms of exercise-induced asthma.[18] Patients received placebo or 30 mg of lycopene (as Lyc-o-mato) for seven days before being crossed over to the other treatment following a four-week washout period. The placebo group had a mean decrease of 26.5% in forced expiratory volume in one second after a seven-minute treadmill run, while the lycopene group had a mean decrease of 14.7% (p < 0.05). The sample was small, so extrapolation of the results to the general population may not be possible. Also Lyc-o-mato has other constituents than lycopene. More must be learned about the possible role of lycopene in patients with exercise-induced asthma.

Lycopene's mechanism of action in affecting prostate health is unknown. Several theories are being explored. The first proposes an association between lycopene and insulin growth factor. High levels of insulin growth factor are linked to a greater risk of prostate cancer; increased lycopene consumption is inversely related to insulin growth factor levels.[3,13]

Another proposed mechanism of action includes both inhibition of tumor growth and increased differentiation of normal cells. Lycopene and other carotenoids cause this inhibition by increasing gap-junctional communication among healthy prostate cells. Malignant prostate cells with a decrease or loss in junctional communication grow more slowly than cells with greater communication.[13,19]

The most widely accepted theory involves lycopene's antioxidant effect.[2] Lycopene acts as a scavenger for singlet oxygens, which are theorized to damage DNA and cause cancer. Lycopene is naturally found in high concentrations in prostate cells, which may account for its specific effect on prostate cancer.[2,13] There is also some evidence that lycopene affects other reactive oxygen species, such as hydrogen peroxide and nitrogen dioxide.

Optimal doses of supplemental lycopene have not yet been determined. Studies have used 15 mg twice daily to decrease the growth rate of prostate cancer. For prostate cancer prevention, epidemiologic studies have suggested that 6 mg/day is beneficial. Most Americans attain this consumption level through their diet. Commercial lycopene products usually contain between 5 and 15 mg of lycopene per capsule. However, the product labeling does not specify whether the lycopene is the all-trans isomer or the cis isomers. An analysis of Lyc-o-mato found that a 15-mg capsule contained 13.5 mg of the all-trans isomer and 1.05 mg of cis isomers.[11]

The bioavailability of lycopene has not been measured, but lycopene appears to be readily absorbed. The processed state of the tomato, the amount of fat in the diet, and the lycopene isomer all influence bioavailability.

Lycopene found naturally in raw (unprocessed) tomatoes is contained within a matrix. Releasing lycopene from this matrix is the first step in absorption.[7] Studies have shown that cooking or heating tomatoes releases the lycopene. For example, fresh tomatoes contain between 30 and 70 mg of lycopene per kilogram, whereas tomato paste contains 300 mg per kilogram.[7,12] Other processed tomato products, such as ketchup and pizza sauce, also contain large amounts of lycopene.[2]

It is generally accepted that some amount of dietary fat is required to absorb lycopene and other carotenoids. One study suggested that at least 5-10 g of fat in a meal is required for lycopene absorption. However, the exact amount of fat required is not known.[7]

Even though most lycopene found in nature is in the all-trans form, most lycopene in the body is in the cis form. This information led researchers to hypothesize that the cis isomers are more readily absorbed. It proved to be very difficult, however, to convert the tomato products to the cis isomers. Heating over long periods of time and processing were tried, with little success.[3,7] A new hypothesis is that a stomach enzyme completes the conversion. A study was conducted in which either a commercially available lycopene powder (in a capsule) or tomato puree was exposed to human gastric juice and simulated gastric juice.[7] The study demonstrated that gastric juice does cause the conversion of the all-trans isomer to the cis isomers. Also, the powder form of lycopene yielded more cis isomers than did tomato puree. The authors suggested a stabilizing effect of the food matrix. The processing to create the powder form eliminates the matrix.

No adverse effects of lycopene use have been reported.[5]

Lycopene is generally considered to be safe. No precautions or contraindications are known at this time.

The only known interaction involving lycopene is enhanced absorption in the presence of β-carotene.[5] Several theoretical interactions have yet to be proven. Canthaxanthin may inhibit lycopene absorption, whereas vitamin D, lutein, and vitamin E may have synergistic effects.[8] Canthaxanthin, often used as a food dye, is a carotenoid but not a precursor of vitamin A. Canthaxanthin supplements are found in oral suntanning agents, the use of which is discouraged by FDA.[5] Nicotine and alcohol affect the levels of other carotenoids; the same may hold true for lycopene. However, some studies imply that alcohol and nicotine do not cause any change in lycopene levels.[8] Lycopene may reduce cholesterol levels and potentiate the effects of statins.

Several studies indicate that lycopene may be of value for prostate cancer prevention and treatment. The ideal dosage of lycopene and the optimum dosage formulation are not known. Dosages from 10 mg once daily to 15 mg twice daily have been studied in patients with prostate cancer; both have been associated with improvement. Current information suggests that as little as 6 mg per day may be useful for prevention. It is likely that this amount of lycopene can easily be achieved through dietary means. However, the type and amount of processing of tomatoes and other food sources of lycopene may make a difference. It appears that processed tomato products, such as tomato sauce and ketchup, contain lycopene with greater bioavailability than that in raw tomatoes; only capsules offer higher bioavailability than processed tomato foods.

No studies have assessed the appropriate age to begin lycopene supplement therapy. Such a study would be difficult to conduct; most lycopene consumption originates from the diet, a variable nearly impossible to control over long periods.

Lycopene has no reported adverse effects, precautions, or contraindications and has relatively few drug interactions, most of which are minor or theoretical.

Lycopene or a diet high in lycopene can safely be recommended for prostate cancer prevention or as adjunctive treatment of prostate cancer. Currently, PSA testing is recommended for men over the age of 50 years who have a life expectancy greater than 10 years and for younger men at high risk of prostate cancer. If the person consumes very few tomato products, supplementation should be started earlier in life. If the person consumes tomato products regularly, supplement therapy could be delayed or may not be necessary.

Lycopene appears safe and may be useful in preventing and treating prostate cancer.

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