Colorectal cancer (CRC) is one of the most common cancers worldwide. Various factors, including oxidative stress, where excessive productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur, contribute to its pathogenesis. Numerous studies have investigated the effect of antioxidant substances derived from food such fruits and vegetables; however, data on Lycopene are still rare. Stidies on HT-29 colorectal cancer cells and on animal models have shown that Lycopene has effects on cell proliferation and on the progression of the CRC by interacting with variuos cellular signaling pathways. this analysis of the literature focused on the antioxidant effect of Lycopene, a substance that is found in the tomato

Battaglia, L.

Cappello, F.

Carini, F.

Damiani, P.

David, S.

Gerges Gergea, A.

Jurjus, A.

Jurjus, R.

Leone, A.

Mazzola, M.

Rappa, F.

Tomasello, G.

CARINI, Francesco

DAVID, Sabrina

TOMASELLO, Giovanni

Mazzola,M

Damiani,P

RAPPA, Francesca

Battaglia,L

CAPPELLO, Francesco

Jurjus,A

Gerges Gergea,A

Jurjus,R

LEONE, Angelo

Archivio istituzionale della ricerca - Università di Palermo

PROOF0393-974X (2017)Copyright © by BIOLIFE, s.a.s.This publication and/or article is for individual use only and may not be furtherreproduced without written permission from the copyright holder.Unauthorized reproduction may result in financial and other penaltiesDISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.99Vol. 31, no. 3, xx-xx (2017)JOURNAL OF BIOLOGICAL REGULATORS & HOMEOSTATIC AGENTSMailing address:Dr. Angelo Leone,BioNec, Section of Histology and Embryology,School of Medicine, University of PalermoVia del Vespro, 129 - 90127 Palermo, ItalyTel.: +390916553582 e-mail: angelo.leone@unipa.itKey words: colorectal cancer, lycopene, oxidative stress, tomato, antioxidant, proliferation, progressionTo the Editor,Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality among adults under 50 years of age in the USA and is one of the most common cancers in the world. It is the third after lung cancer and breast cancer, and has a multifactorial pathogenesis. Various factors contribute to the development of CRC, such as environmental factors, chronic inflammatory bowel disease (Crohn’s disease and ulcerative colitis), genetic factors and lifestyle (such as diet). Combined factors result in an alteration of the intestinal flora (knownb as dysbiosis), and a release of inflammatory mediators and heat shock proteins (HSP) (1, 2), resulting in the establishment of a chronic inflammatory process (3, 4). These factors, combined with dysbiosis and inflammatory processes (5), contribute to an increase of oxidative stress, reactive oxygen and COLORECTAL CANCER: AN UPDATE ON THE EFFECTS OF LYCOPENE ON TUMOR PROGRESSION AND CELL PROLIFERATIONF. CARINI1*, S. DAVID1*, G. TOMASELLO1-2*,M. MAZZOLA1-2*, P. DAMIANI3,F. RAPPA1-2, L. BATTAGLIA5, F. CAPPELLO1-2, A. JURJUS6, A. GERGES GEAGEA1-6, R. JURJUS7 and A. LEONE81Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, (BIONEC), University of Palermo, Italy; 2Euro Mediterranean Institute of Science and Technology – IEMEST Palermo, Italy; 3AOUP “P. Giaccone”, School of Medicine and Surgery, University of Palermo, Italy; 4Fondazione Istituto S. Raffaele - G. Giglio, Gastroenterology and Endoscopy Unit, Cefalù, Italy; 5Istituto Zooprofilattico Sperimentale della Sicilia, Palermo, Italy; 6Department of Anatomy Cell Biology and Physiological Science, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 7Department of Anatomy and Regenerative Biology, George Washington School of Medicine and Health Sciences, Washington, USA; 8Department of Experimental Biomedicine and Clinical Neuroscience, Section of Histology and Embryology, (BIONEC), University of Palermo, ItalyReceived May 31, 2017 – Accepted June 28, 2017*These authors contributed equally to the workColorectal cancer (CRC) is one of the most common cancers worldwide. Various factors, including oxidative stress, where excessive productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur, contribute to its pathogenesis. Numerous studies have investigated the effect of antioxidant substances derived from food such as fruits and vegetables; however, data on Lycopene are still rare. Studies on HT-29 colorectal cancer cells and on animal models have shown that lycopene has effects on cell proliferation and on the progression of the CRC by interacting with various cellular signaling pathways. This analysis of the literature focused on the antioxidant effect of lycopene, a substance that is found in the tomato.LETTER TO THE EDITORPROOFPROOF100intervene with the proliferation of cancer cells and with the blocking of their oncogenetic transformation (8). This update is focused on Lycopene, one of the most important exogenous antioxidants.Lycopene Lycopene is a lipophilic pigment responsible for the red color in tomatoes with concentrations ranging from 0.9 to 9.27 mg/100g, according to the variety and ripeness of the tomato (9, 10). Chemically, it is an isomer of beta-carotene, with the chemical formula C40H56, and contains a hydrocarbon chain without any functional group (8-10). In fact, thanks to the number of conjugated double bonds present in its chemical structure, lycopene is a powerful antioxidant. It is able to counteract the ROS, such as singlet oxygen and peroxyl radicals (8, 10, 12).  Lycopene antioxidant action is expressed at different levels by:- inducing the detoxification processes through nitrogen species (ROS/RNS) (3). Oxidative stress arises from an imbalance between the oxidizing and the antioxidant species. ROS (such as hydrogen peroxide, hydroxyl radical, superoxide anion and peroxynitrite), cause structural alterations on cell membranes (such as lipid peroxidation) and on DNA (such as genetic instability, point mutations, deletions, insertions and aneuploidy). ROS represents one of the key factors involved in the development of CRC (3, 6, 7).Among the genes activated by oxidative stress, and implicated in the genesis of colorectal cancer, are hypoxia-inducible factor-1A (HIFIA) and inducible nitric oxide synthase (NOS2A). Both genes increase the production of pro-inflammatory cytokines (7).  Therefore, to reduce or inhibit carcinogenesis linked to oxidative stress, a strategy known as “chemoprevention” needs to be adopted which involves the administration of exogenous compounds, usually contained in fruits and vegetables, which Fig. 1. Antioxidant effects of lycopene. The action of the substance takes place at the enzymatic level on glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and cytochrome P450 2E1 (CYP2E1), and at a nuclear level,  on antioxidant response element (ARE).F. CARINI ET AL.PROOF101Journal of Biological Regulators & Homeostatic Agentsmetalloproteinase (MMP)-2 (13).Another study on metalloproteinases, in particular of MMP-7, showed how MMP-7 was highly expressed in CRC cells and involved in tumor progression, development of angiogenesis and metastasis. This study, performed on HT-29 colorectal cancer cell line, investigated the effect of lycopene on the expression levels of leptin, the high plasma concentrations of which seem to be related to increased tumor progression and linked to increased expression of MMP-7. It also demonstrated that increasing concentrations of lycopene inhibit the expression of MMP-7 through inhibition of leptin-mediated phosphorylation of molecules belonging to the signaling pathway phosphoinositide 3-kinase (PIK3)/Akt and MAPK/ERK (14).In reference to other signaling pathways, many authors have supported a correlation between administration of lycopene and changes in the biosynthetic pathway of cholesterol in the tumor cells, with consequent reduction of the activation of Ras pathway. Colon cancer cell lines HT-29 and HCT-116 with mutated Ras, were cultured with 10 µm of lycopene for 24 hours. The results showed that lycopene reduced the cell growth by reducing the expression of HmgCoA-reductase and by increasing the translocation of Ras from the plasma membrane to the cytosol (14). In this respect, the following four studies are of particular interest (16-19).The first study, carried out on HT-29 colorectal cancer cell lines, focused on the importance of the signaling pathways of PI3K/Akt. This signaling pathway when activated in a continuous mode is involved in both tumor cell proliferation and in the development of angiogenesis. Lycopene appeared to inhibit, in a dose-dependent manner, the PIK3/Akt pathway by interfering with the phosphorylation processes and, thereby, reducing the activation of Akt. Lycopene also inhibited the activity of cyclin D1 and interfered with the processes of activation of cyclin-dependent kinase inhibitor p27kip (16).The second study, using again the HT-29 colorectal cancer cell lines in xenograft mice models, showed that lycopene has inhibitory effects on the growth and progression of CRC. In particular, the study documented that lycopene inhibited the the production of enzymes of phase I and II. In particular, it is documented that lycopene stimulates the activity of enzymes such as glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) (8, 10). The detoxification processes are also induced at the nuclear level, through the action of the transcription factor nuclear factor E2-related factor 2 (Nrf2), which belongs to the antioxidant response element (ARE) family (8);- exerting an inhibitory effect on cytochrome P450 2E1 (CYP2E1) which is responsible for the conversion of xenobiotics in carcinogenic substances (10) (Fig. 1).The lycopene also plays a role in anti-inflammatory activity, which results in the suppression of promotion and progression of carcinogenesis and inhibition of cell invasion, angiogenesis and metastasis (7).   This inhibitory effect is expressed on: - growth factors such as insulin-like growth factor 1 (IGF-1). Lycopene inhibits the binding to the receptor by increasing the production of IGFBP-1 and IGFBP-2) (8);- angiogenesis, through the inhibition of matrix metalloproteinase (MMP)-2 and the urokinase plasminogen activator (uPA), which have a central role in the metastatic process (8);- cell cycle by inducing the arrest in G1/S phase and inactivation of the Ras signaling pathway (8);- apoptosis by reducing the expression of the anti-apoptotic molecule Bcl-2 and increasing the activity of caspase 3 and 8 and the pro-apoptotic factors Bax and Bim (8).  Analysis of literature There are numerous studies, mostly carried out in vitro, depicting the antitumor activity of lycopene, with particular reference to CRC. The first in vitro study highlighted the action of lycopene on the growth of colorectal cancer cell line HT-29. Lycopene, used in combination with gold nanoparticles as a vehicle, was able to reduce the expression of pro-caspase 3, 8 and 9 and Bcl-2 and PARP-1, and to increase the expression of molecules such as Bax, thus favoring the apoptotic process. In addition, there was a drastic reduction of cell migration capacity, linked to downregulation of Akt, nuclear factor kappa B, and PROOFPROOF102lycopene, in associaton with Bifidobacterium lactisplus and oligofructose/inulin, and the expression of ACF. The study showed that lycopene supplementation (300 mg/kg body weight) for two weeks in mice previously treated with carcinogenic substances (such as 1,2-dimethylhydrazine), decreased the formation of classical and mucin-negative ACF, increased apoptosis, and reduced the rates of PCNA and p53-positive cells (20).Another study, using the HT-29 colorectal cancer cell line and xenograft mice models, investigated the association between lycopene and eicosapentaenoic acid (EPA) contained in fish oil. The studies demonstrated that the association lycopene/EPA reduced tumor growth and progression through increased expression of cell cycle inhibitors (such as p21Cip1/WAF1 and p27Kip1), suppressed by molecules related to cell proliferation (such as MMP-7, MMP-9, COX-2, PGE2, β-catenin, cyclin D1 growth of cancer cells in CRC-bearing mice by inducing apoptosis, suppressing the expression of PCNA, modulating the expression of β-catenin and E-cadherin and up-regulating the inhibitory proteins p21Cip1/WAF1 (17) (Fig. 2). Synergistic effect of lycopeneAdditional studies showed the synergistic action of lycopene in association with other substances. Lycopene studies in combination with other substances date back to the early 1990s. Two studies, performed in 1996 and 1998, showed how the association between lycopene, alpha-carotene, beta-carotene, lutein, and curcumin, reduced the expression of early lesions in CRC, such as aberrant Crypt foci (ACF) in mice treated with N-methylnitrosourea (18) or 1,2-dimethylhydrazine (19).A similar study was conducted many years later and shows the correlation between the consumption of Fig. 2. Anticancer effect of lycopene. From literature studies, lycopene shows pro-apoptotic action by reducing the expression of anti-apoptotic molecules such as BCL-2, and increasing the production of proapoptotic molecules such as BAX. It also shows antiangiogenic and anti-metastatic action, through interference with the PIK3/Akt pathway and metalloproteinase inhibition (MMP-7). Finally, it reduces cell proliferation by inhibiting the activity of cyclin D1 and causing cell cycle arrest in the G1 / S phase.F. CARINI ET AL.PROOF103Journal of Biological Regulators & Homeostatic Agentsbowel disease and colorectal cancer,  nutraceutical aspects. Euromediterranean biomedical journal 2016; 11(17):123-294. Tomasello G, Tralongo P, Damiani P, et al. Dismicrobism in inflammatory bowel disease and colorectal cancer: changes in response of colocytes. World J Gas-troenterol 2014;  20(48):18121-30. 5. Scardina GA, Pisano T, Carini F, Valenza V, Messina P. Burning mouth syndrome: an evaluation of in vivo microcirculation. J Am Dent Assoc 2008; 139(7):940-46.6. Tomasello G, Mazzola M, Leone A, et al. Nutrition, oxidative stress and intestinal dysbiosis: Influence of diet on gut microbiota in inflammatory bowel diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016; 160(4):461-66.7. Slattery ML, Lundgreen A, Welbourn B, Wollf RK, Corcoran C. Oxidative balance and colon and rectal cancer: interaction of lifestyle factors and genes. Mutat Res 2012; 734(1-2):30-40.8. Trejo-Solís C, Pedraza-Chaverrí J, Torres-Ramos M, et al. Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition. Evid Based Complement Alternat Med 2013; 2013:705121.9. Milani A, Basirnejad M, Shahbazi S, Bolhassani A. Carotenoids: biochemistry, pharmacology and treatment.  Br J Pharmacol 2017; 174(11):1290-324.10. Bandeira AC, da Silva TP, de Araujo GR, et . Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice. Chem Biol Interact 2016; 263:7-17.11. Sahin K, Orhan C, Tuzcu M, Sahin N, Hayirli A, Bilgili S, Kucuk O. Lycopene activates antioxidant enzymes and nuclear transcription factor systems in heat-stressed broilers. Poult Sci 2016; 95(5):1088-95.12. Boehm F, Edge R, Truscott TG, Witt C. A dramatic effect of oxygen on protection of human cells against γ-radiation by lycopene. Febs Lett 2016; 590(8):1086-93.13. Huang RF, Wei YJ, Inbaraj BS, Chen BH. Inhibition of colon cancer cell growth by nanoemulsion carrying gold nanoparticles and lycopene. Int J Nanomedicine 2015; 10:2823-46.14. Lin MC, Wang FY, Kuo YH, Tang FY. Cancer and c-Myc) (21), suppressed by PI-3K/Akt/ mTOR pathways, and induction of the expression of Bax proteins and Fas ligand proteins (22).Finally, some studies have shown that the association with other antioxidants, such as α-carotene, β-carotene, lutein, and Vitamin E, is correlated with lycopene. It has been seen that this entire mixture of antioxidants inhibits liposome oxidation to a greater extent than the intake of individual antioxidants (23).CONCLUSIONSMost studies on the antioxidant and antitumoral activity of lycopene were performed on animal models or CRC cell lines, therefore, to date, the data from these studies cannot be translated to humans. Targeted studies on lycopene, taken as a dietary supplement, such as a primary or a secondary prevention measure of CRC in human subjects are required. It is also necessary that subsequent studies need to focus on the amount or dose of lycopene that actually works as an active ingredient, once taken orally, so as to create food supplements, a nutraceutical that can provide an adequate amount of active ingredient to give the desired preventive effect. It is also our view to assume a working hypothesis concerning the correlation between the intake of lycopene and the state of eubiosis of human microbiota. In particular, it would be useful to know the influence of lycopene on a dysbiotic intestinal mucosa, and its possible ability to restore eubiosis of intestinal microbiota, thus preventing or blocking the chain of events that lead to ACF formation and, consequently, CRC.REFERENCES1. Rappa F, Sciume C, Lo Bello M, et al. Comparative analysis of Hsp10 and Hsp90 expression in healthy mucosa and adenocarcinoma of the large bowel. Anticancer Res 2014; 34(8):41535-9.2. Cappello F, Conway de Macario E, Marino Gammazza A, et al. Hsp60 and human aging: Les liaisons dangereuses. Front Biosci (Landmark Ed). 2013; 18:626-37.3. Mazzola M, Carini F, Leone A, et al.  Inflammatory PROOFPROOF10419. Kim JM, Araki S, Kim DJ, et al. Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis 1998; 19(1):81-85.20. Dias MC, Vieiralves NF, Gomes MI, Salvadori DM, Rodrigues MA, Barbisan LF. Effects of lycopene, synbiotic and their association on early biomarkers of rat colon carcinogenesis. Food Chem Toxicol 2010; 48(3):772-80.21. Tang FY, Pai MH, Kuo YH, Wang XD. Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer. Mol Nutr Food Res 2012; 56(10):1520-31.22. Tang FY, Cho HJ, Pai MH, Chen YH. Concomitant supplementation of lycopene and eicosapentaenoic acid inhibits the proliferation of human colon cancer cells. J Nutr Biochem 2009; 20(6):426-34.23. Shi J, Kakuda Y, Yeung D. Antioxidative properties of lycopene and other carotenoids from tomatoes: synergistic effects. Biofactors. 2004; 21(1-4):203-10.chemopreventive effects of lycopene: suppression of MMP-7 expression and cell invasion in human colon cancer cells. J Agric Food Chem 2011; 59(20):11304-18.15. Palozza P, Colangelo M, Simone R, et al. Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis 2010; 31(10):1813-21.16. Tang FY, Shih CJ, Cheng LH, Ho HJ, Chen HJ. Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Mol Nutr Food Res 2008; 52(6):646-54.17. Tang FY, Pai MH, Wang XD. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model. J Agric Food Chem 2011; 59(16):9011-21. 18. Narisawa T, Fukaura Y, Hasebe M, et al. Inhibitory effects of natural carotenoids, alpha-carotene, beta-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer Lett 1996; 107(1):137-42.F. CARINI ET AL.

COLORECTAL CANCER: AN UPDATE ON THE EFFECTS OF LYCOPENE ON TUMOR PROGRESSION AND CELL PROLIFERATION

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COLORECTAL CANCER: AN UPDATE ON THE EFFECTS OF LYCOPENE ON TUMOR PROGRESSION AND CELL PROLIFERATION

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