Lycopene Abstracts 1

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Lycopene. Monograph

         (2003) Download

Tomato lycopene and its role in human health and chronic diseases

         (Agarwal and Rao 2000) Download        

Lycopene is a carotenoid that is present in tomatoes, processed tomato products and other fruits. It is one of the most potent antioxidants among dietary carotenoids. Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease. Serum and tissue lycopene levels have been found to be inversely related to the incidence of several types of cancer, including breast cancer and prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial effects, evidence is accumulating to suggest that other mechanisms may also be involved. In this article we outline the possible mechanisms of action of lycopene and review the current understanding of its role in human health and disease prevention.

Cutaneous concentration of lycopene correlates significantly with the roughness of the skin

         (Darvin, Patzelt et al. 2008) Download

Antioxidant substances in the skin are expected to slow down photo ageing. We therefore developed the hypothesis that high levels of antioxidant substances may be correlated to lower levels of skin roughness. By utilizing modern optical non-invasive in vivo methods, the structures of the furrows and wrinkles as well as the concentration of lycopene were analyzed quantitatively on the forehead skin of 20 volunteers aged between 40 and 50 years. In a first step, the age of the volunteers was correlated to their skin roughness. Here, no significant correlation was found. In a second step, a significant correlation was obtained between the skin roughness and the lycopene concentration (R=0.843). These findings indicate that higher levels of antioxidants in the skin effectively lead to lower levels of skin roughness, and therefore support our hypothesis.

Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease

         (Elson 1995) Download

Diet-cancer and diet-cardiovascular disease interrelationships may be explained by the mevalonate-suppressive action of isoprenoid end products of plant secondary metabolism. Assorted monoterpenes, sesquiterpenes, carotenoids and tocotrienols posttranscriptionally down regulate 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, a key activity in the sterologenic pathway. The modest decrease in cholesterol synthesis is associated with a concomitant lowering of low-density lipoprotein cholesterol. The reductase activity in tumor tissues differs from that of liver in being resistant to sterol feedback regulation. Tumor reductase activity retains sensitivity to posttranscriptional regulation. As a consequence, the isoprenoid-mediated suppression of mevalonate synthesis depletes tumor tissues of two intermediate products, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are incorporated posttranslationally into growth control-associated proteins. At 10-fold higher concentrations, monoterpenes inhibit the protein isoprenyl transferases that catalyze this incorporation. At levels of intake likely provided by a diet based on Food Pyramid guidelines, assorted isoprenoids decrease cardiovascular disease risk and suppress the growth of initiated cells. At pharmacological levels of intake, isoprenoids block the initiation phase of chemical carcinogenesis. Isoprenoids targeted to the inhibition of the isoprenylation of oncogenic forms of ras proteins may offer a novel approach to chemotherapy. Adjunctive isoprenoids might decrease the level of competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase required to manage hypercholesterolemia.


Anticarcinogenic, Cardioprotective, and Other Health Benefits of Tomato Compounds Lycopene, alpha-Tomatine, and Tomatidine in Pure Form and in Fresh and Processed Tomatoes

         (Friedman 2013) Download

Tomatoes produce the bioactive compounds lycopene and alpha-tomatine that are reported to have potential health-promoting effects in animals and humans, but our understanding of the roles of these compounds in the diet is incomplete. Our current knowledge gained from the chemistry and analysis of these compounds in fresh and processed tomatoes and from studies on their bioavailability, bioactivity, and mechanisms of action against cancer cells and other beneficial bioactivities including antibiotic, anti-inflammatory, antioxidative, cardiovascular, and immunostimulating effects in cells, animals, and humans is discussed and interpreted here. Areas for future research are also suggested. The collated information and suggested research might contribute to a better understanding of the agronomical, biochemical, chemical, physiological, molecular, and cellular bases of the health-promoting effects and facilitate and guide further studies needed to optimize the use of lycopene and alpha-tomatine in pure form and in fresh tomatoes and processed tomato products to help prevent or treat human disease.

Lycopene ameliorates erectile dysfunction in streptozotocin-induced diabetic rats

         (Gao, Li et al. 2012) Download

Diabetes mellitus (DM) is characterized by oxidative stress, which is one of the major pathophysiological mechanisms underlying diabetic erectile dysfunction (ED). Lycopene is one of the most potent antioxidants among the natural carotenoids. The present study was aimed to investigate whether lycopene could lower oxidative stress and attenuate ED in diabetic rats. Lycopene (10, 30, 60 mg/kg/d) was administered via intragastric intubation for 8 weeks to streptozotocin (STZ) (50 mg/kg, i.v.) induced diabetic rats. The results showed that chronic lycopene treatment significantly and dose dependently restored ED in diabetic rats by lowering blood glucose, reducing oxidative stress and up-regulating eNOS expression. These results indicated that lycopene treatment is potentially a new strategy for treating diabetic ED.


Serum carotenoids reduce progression of early atherosclerosis in the carotid artery wall among Eastern Finnish men

         (Karppi, Kurl et al. 2013) Download

BACKGROUND: Several previous epidemiologic studies have shown that high blood levels of carotenoids may be protective against early atherosclerosis, but results have been inconsistent. We assessed the association between atherosclerotic progression, measured by intima-media thickness of the common carotid artery wall, and serum levels of carotenoids. METHODS: We studied the effect of carotenoids on progression of early atherosclerosis in a population-based study. The association between concentrations of serum carotenoids, and intima-media thickness of the common carotid artery wall was explored in 840 middle-aged men (aged 46-65 years) from Eastern Finland. Ultrasonography of the common carotid arteries were performed at baseline and 7-year follow-up. Serum levels of carotenoids were analyzed at baseline. Changes in mean and maximum intima media thickness of carotid artery wall were related to baseline serum carotenoid levels in covariance analyses adjusted for covariates. RESULTS: In a covariance analysis with adjustment for age, ultrasound sonographer, maximum intima media thickness, examination year, body mass index, systolic blood pressure, smoking, physical activity, serum LDL cholesterol, family history of coronary heart disease, antihypertensive medication and serum high sensitivity C-reactive protein, 7-year change in maximum intima media thickness was inversely associated with lycopene (p = 0.005), alpha-carotene (p = 0.002) and beta-carotene (p = 0.019), respectively. CONCLUSIONS: The present study shows that high serum concentrations of carotenoids may be protective against early atherosclerosis.

Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals

         (McEneny, Wade et al. 2013) Download

The management of overweight subjects by interventions aimed at reducing inflammation is highly desirable. To date, observational studies have identified a link between increased dietary antioxidant intake and reduced cardiovascular morbidity. However, direct trial evidence regarding the ability of antioxidants to influence inflammation is lacking. Therefore, this study examined lycopene's ability to lower systemic and high-density lipoprotein (HDL)-associated inflammation in moderately overweight middle-aged subjects. Serum was collected before and after a 12-week intervention from 54 moderately overweight, middle-aged individuals. Subjects were randomised to one of three groups: control diet (<10 mg lycopene/week), lycopene-rich diet (224-350 mg lycopene/week) and lycopene supplement (70 mg lycopene/week). HDL was subfractionated into HDL(2&3) by rapid ultracentrifugation. Compliance was monitored by assessing lycopene concentration in serum and HDL(2&3). Systemic and HDL-associated inflammation was assessed by measuring serum amyloid A (SAA) levels. HDL functionality was determined by monitoring the activities of paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT). Lycopene increased in serum and HDL(2&3) following both lycopene interventions (P<.001, for all), while SAA decreased in serum following the lycopene supplement and in HDL(3) following both lycopene interventions (P<.05 for all). PON-1 activity increased in serum and HDL(2&3) in both lycopene groups (P<.05, for all). Furthermore, the activity of CETP decreased in serum following the lycopene supplement, while the activity of LCAT increased in serum and HDL(3) following both lycopene interventions (P<.05 for all). These results demonstrate that in moderately overweight, middle-aged subjects, increasing lycopene intake leads to changes to HDL(2&3), which we suggest enhanced their antiatherogenic properties. Overall, these results show the heart-protective properties of increased lycopene intake.

The effect of lycopene treatment on ACE activity in rats with experimental diabetes

         (Ozmutlu, Dede et al. 2012) Download

In this study, the anti-inflammatory and antioxidant known as lycopene was applied to rats with experimental diabetes with the aim of investigating the detection of diabetes-related complications, and to determine the possible role of lycopene in diabetes complications regarding the effects of ACE activity. In order to induce diabetes in rats in the diabetes (D) and diabetes+lycopene (DL) groups, rats were given 45 mg/kg single-dose streptozotocin (STZ) intraperitoneally (i.p.); lycopene (10 mg/kg/day dissolved in sunflower oil) was administered to the rats in the lycopene-only (L) and DL groups. Blood glucose levels and HbA1c% in diabetes+lycopene group and diabetes group increased (p <0.05) compared to control and only lycopene treated group. The highest level of ACE activity was observed in the (D) group (p < 0.05). Activity in the (L) group was also significantly greater than in the control group (p < 0.05). The (DL) group had lower (p < 0.05). ACE activity than the (D) group. Lycopene implementation was found to be effective in the inhibition of ACE activity, an important indicator of diabetes-related complications.

Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines

         (Palozza, Colangelo et al. 2010) Download

Several evidences suggest that cancer cells have abnormal cholesterol biosynthetic pathways and prenylation of small guanosine triphosphatase proteins. Tomato lycopene has been suggested to have beneficial effects against certain types of cancer, including that of prostate, although the exact molecular mechanism(s) is unknown. We tested the hypothesis that lycopene may exert its antitumor effects through changes in mevalonate pathway and in Ras activation. Incubation of the Ras-activated prostatic carcinoma LNCaP cells with a 24 h lycopene treatment (2.5-10 muM) dose dependently reduced intracellular total cholesterol by decreasing 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase expression and by inactivating Ras, as evidenced by its translocation from cell membranes to cytosol. Concomitantly, lycopene reduced the Ras-dependent activation of nuclear factor-kappaB (NF-kappaB). Such a reduction was parallel to an inhibition of reactive oxygen species production and to a decrease in the phosphorylation ofc-jun N-terminal kinase, extracellular signal-regulated kinase 1/2 and p38. These effects were also accompanied by an arrest of cell cycle progression and by apoptosis induction, as evidenced by a decrease in cyclin D1 and phospho-AKT levels and by an increase in p21, p27 and p53 levels and in Bax:Bcl-2 ratio. The addition of mevalonate prevented the growth-inhibitory effects of lycopene as well as its increase in Ras cytoplasmatic accumulation and the subsequent changes in NF-kappaB. The ability of lycopene in inhibiting HMG-CoA reductase expression and cell growth and in inactivating Ras was also found in prostate PC-3, colon HCT-116 and HT-29 and lung BEN cancer cells. These findings provide a novel mechanistic insight into the growth-inhibitory effects of lycopene in cancer.


Lycopene regulation of cholesterol synthesis and efflux in human macrophages

         (Palozza, Simone et al. 2011) Download

Hypercholesterolemia is one of the most important risk factors for atherosclerosis, and tomato lycopene has been suggested to have beneficial effects against such a disease, although the exact molecular mechanism is unknown. We tested the hypothesis that lycopene may exert its antiatherogenic role through changes in cholesterol metabolism. Incubation of THP-1 cells with lycopene (0.5-2 muM) dose-dependently reduced intracellular total cholesterol. Such an effect was associated with a decrease in reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase expression and with an increase in ABCA1 and caveolin-1 (cav-1) expressions. In addition, lycopene enhanced RhoA levels in the cytosolic fraction, activating peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha expressions. Concomitant addition of lycopene and the PPARgamma inhibitor GW9662 or lycopene and mevalonate blocked the carotenoid-induced increase in ABCA1 and cav-1 expressions. These results imply a potential role of lycopene in attenuating foam cell formation and, therefore, in preventing atherosclerosis by a cascade mechanism involving inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase, RhoA inactivation and subsequent increase in PPARgamma and liver X receptor alpha activities and enhancement of ABCA1 and cav-1 expressions.

Effect of lycopene and tomato products on cholesterol metabolism

         (Palozza, Catalano et al. 2012) Download

BACKGROUND/AIMS: Increased ingestion of tomato, containing lycopene, has been associated with a decreased risk for atherosclerosis, although the exact molecular mechanism is still unknown. Here we review the available evidence for a direct regulation of tomato lycopene on cholesterol metabolism using results from experimental and human studies. RESULTS: In human macrophages lycopene dose dependently reduced intracellular total cholesterol. Such an effect was associated with a decrease in cholesterol synthesis through a reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and expression, a modulation of low- density lipoprotein (LDL) receptor and acyl-coenzyme A:cholesterol acyltransferase activity. An increase in cholesterol efflux through an enhancement of ABCA1 and caveolin-1 expression was also observed. In animal models of atherosclerosis, lycopene and tomato products decreased plasma total cholesterol, LDL cholesterol and increased high-density lipoprotein cholesterol. In agreement with the experimental results, most human intervention trials analyzed show that dietary supplementation with lycopene and/or tomato products reduced plasma LDL cholesterol dependently on the dose and the time of administration. CONCLUSIONS: Although lycopene and tomato products seem to possess direct hypocholesterolemic properties, more experimental studies are needed to better understand the mechanisms involved. There is also a need for more well-designed human dietary intervention studies to better clarify the role of lycopene as a hypocholesterolemic agent.

Protective effects of lycopene against amyloid beta-induced neurotoxicity in cultured rat cortical neurons

         (Qu, Li et al. 2011) Download

The neurotoxicity of amyloid beta (Abeta) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD). Among antioxidant phytochemicals derived from fruit and vegetables, lycopene has recently received considerable attention for its potent protective properties already demonstrated in several models of oxidative damage. The present study aims to investigate whether lycopene could provide protective effects against Abeta-induced neurotoxicity in primary cultured rat cortical neurons. The cultured cortical neurons were pretreated with different dose of lycopene for 4h, followed by the challenge with 25 muM Abeta(25-35) for 24h. The results showed that pretreatment with lycopene efficiently attenuated Abeta(25-35)-induced neurotoxicity, as evidenced by the improved cell viability and the decreased apoptotic rate. In addition, lycopene inhibited the reactive oxygen species generation and mitochondrial membrane potential depolarization caused by Abeta(25-35). Lycopene also restored the levels of proapoptotic Bax, antiapoptotic Bcl-2, and inhibited caspase-3 activation. These beneficial effects may contribute to the protection against Abeta-induced neurotoxicity. Together, our results suggest that the natural antioxidant lycopene has potential for neuroprotection and therefore, may be a promising candidate for AD treatment.


Effect of lycopene on cell viability and cell cycle progression in human cancer cell lines

         (Teodoro, Oliveira et al. 2012) Download

BACKGROUND: Lycopene, a major carotenoid component of tomato, has a potential anticancer activity in many types of cancer. Epidemiological and clinical trials rarely provide evidence for mechanisms of the compound's action, and studies on its effect on cancer of different cell origins are now being done. The aim of the present study was to determine the effect of lycopene on cell cycle and cell viability in eight human cancer cell lines. METHODS: Human cell lines were treated with lycopene (1-5 muM) for 48 and 96 h. Cell viability was monitored using the method of MTT. The cell cycle was analyzed by flow cytometry, and apoptotic cells were identified by terminal deoxynucleotidyl transferase-mediated dUTP nick labeling (TUNEL) and by DAPI. RESULTS: Our data showed a significant decrease in the number of viable cells in three cancer cells lines (HT-29, T84 and MCF-7) after 48 h treatment with lycopene, and changes in the fraction of cells retained in different cell cycle phases. Lycopene promoted also cell cycle arrest followed by decreased cell viability in majority of cell lines after 96 h, as compared to controls. Furthermore, an increase in apoptosis was observed in four cell lines (T-84, HT-29, MCF-7 and DU145) when cells were treated with lycopene. CONCLUSIONS: Our findings show the capacity of lycopene to inhibit cell proliferation, arrest cell cycle in different phases and increase apoptosis, mainly in breast, colon and prostate lines after 96 h. These observations suggest that lycopene may alter cell cycle regulatory proteins depending on the type of cancer and the dose of lycopene administration. Taken together, these data indicated that the antiproliferative effect of lycopene was cellular type, time and dose-dependent.

Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition

         (Trejo-Solis, Pedraza-Chaverri et al. 2013) Download

Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

Multitargeted therapy of cancer by lycopene

         (van Breemen and Pajkovic 2008) Download

Lycopene (psi,psi-carotene) is the most abundant carotenoid in tomatoes and is the red pigment of not only tomatoes but also rosehips, watermelon, papaya, pink grapefruit, and guava. Unlike beta-carotene, lycopene lacks a beta-ionone ring and therefore has no pro-vitamin A activity. However, the 11 conjugated and two non-conjugated double bonds in lycopene make it highly reactive towards oxygen and free radicals, and this anti-oxidant activity probably contributes to its efficacy as a chemoprevention agent. The reactivity of lycopene also explains why it isomerizes rapidly in blood and tissues from the biosynthetic all-trans form to a mixture of cis-isomers. Prospective and retrospective epidemiological studies indicating an inverse relationship between lycopene intake and prostate cancer risk have been supported by in vitro and in vivo experiments showing that oral lycopene is bioavailable, accumulates in prostate tissue and is localized to the nucleus of prostate epithelial cells. In addition to antioxidant activity, in vitro experiments indicate other mechanisms of chemoprevention by lycopene including induction of apoptosis and antiproliferation in cancer cells, anti-metastatic activity, and the upregulation of the antioxidant response element leading to the synthesis of cytoprotective enzymes. Lycopene is a substrate for carotene-9',10'-monooxygenase (CMO2) and can be converted to apo-10'-carotenal. Although Phase I and II studies have been published that establish the safety of lycopene supplementation, carefully designed and adequately powered clinical studies of lycopene are still needed to confirm its efficacy as a chemoprevention agent.


References

(2003). "Lycopene. Monograph." Altern Med Rev 8(3): 336-42. [PMID: 12946243]

Agarwal, S. and A. V. Rao (2000). "Tomato lycopene and its role in human health and chronic diseases." CMAJ 163(6): 739-44. [PMID: 11022591]

Darvin, M., A. Patzelt, et al. (2008). "Cutaneous concentration of lycopene correlates significantly with the roughness of the skin." Eur J Pharm Biopharm 69(3): 943-7. [PMID: 18411044]

Elson, C. E. (1995). "Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease." J Nutr 125(6 Suppl): 1666S-1672S. [PMID: 7782923]

Friedman, M. (2013). "Anticarcinogenic, Cardioprotective, and Other Health Benefits of Tomato Compounds Lycopene, alpha-Tomatine, and Tomatidine in Pure Form and in Fresh and Processed Tomatoes." J Agric Food Chem 61(40): 9534-50. [PMID: 24079774]

Gao, J. X., Y. Li, et al. (2012). "Lycopene ameliorates erectile dysfunction in streptozotocin-induced diabetic rats." Pharmazie 67(3): 256-9. [PMID: 22530309]

Karppi, J., S. Kurl, et al. (2013). "Serum carotenoids reduce progression of early atherosclerosis in the carotid artery wall among Eastern Finnish men." PLoS One 8(5): e64107. [PMID: 23700460]

McEneny, J., L. Wade, et al. (2013). "Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals." J Nutr Biochem 24(1): 163-8. [PMID: 22819555]

Ozmutlu, S., S. Dede, et al. (2012). "The effect of lycopene treatment on ACE activity in rats with experimental diabetes." J Renin Angiotensin Aldosterone Syst 13(3): 328-33. [PMID: 22588536]

Palozza, P., A. Catalano, et al. (2012). "Effect of lycopene and tomato products on cholesterol metabolism." Ann Nutr Metab 61(2): 126-34. [PMID: 22965217]

Palozza, P., M. Colangelo, et al. (2010). "Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines." Carcinogenesis 31(10): 1813-21. [PMID: 20699249]

Palozza, P., R. Simone, et al. (2011). "Lycopene regulation of cholesterol synthesis and efflux in human macrophages." J Nutr Biochem 22(10): 971-8. [PMID: 21208793]

Qu, M., L. Li, et al. (2011). "Protective effects of lycopene against amyloid beta-induced neurotoxicity in cultured rat cortical neurons." Neurosci Lett 505(3): 286-90. [PMID: 22044877]

Teodoro, A. J., F. L. Oliveira, et al. (2012). "Effect of lycopene on cell viability and cell cycle progression in human cancer cell lines." Cancer Cell Int 12(1): 36. [PMID: 22866768]

Trejo-Solis, C., J. Pedraza-Chaverri, et al. (2013). "Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition." Evid Based Complement Alternat Med 2013: 705121. [PMID: 23970935]

van Breemen, R. B. and N. Pajkovic (2008). "Multitargeted therapy of cancer by lycopene." Cancer Lett 269(2): 339-51. [PMID: 18585855]