Naturally occurring hydroxytyrosol: Synthesis and anticancer potential

Current Medicinal Chemistry

Volumn 20, Issue 5, 2013, Pages 655-670

  Bernini, R ^a   Merendino, N ^a   Romani, A ^b   Velotti, F ^a,c  

^a UNIVERSITY OF TUSCIA   (Italy)

^b UNIVERSITY OF FLORENCE   (Italy)

^c REGINA ELENA NATIONAL CANCER INSTITUTE   (Italy)

Author keywords

Anti cancer activity; Cancer; Carcinogenesis; Hydroxytyrosol; Inflammation; Olive mill; Olive oil wastewaters; Oxidation; Polyphenols; Proliferation; Signaling; Synthesis

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; ANTIOXIDANT; CYCLOOXYGENASE 2; ECHINACOSIDE; GENOMIC DNA; HYDROXYTYROSOL; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; INTERLEUKIN 6; LIPOXYGENASE; OLEUROPEIN; PROSTAGLANDIN SYNTHASE; REACTIVE OXYGEN METABOLITE; TUMOR NECROSIS FACTOR;

ANTIINFLAMMATORY ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; CANCER THERAPY; CARCINOGENESIS; CELL DAMAGE; CELL PROLIFERATION; CELL STRAIN MCF 7; CHEMOPROPHYLAXIS; DRUG SYNTHESIS; ENDOPLASMIC RETICULUM; HUMAN; IMMUNE SYSTEM; IN VITRO STUDY; NONHUMAN; OXIDATION; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 84877979324     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986713804999367     Document Type: Article

References (156)

1. Stoll, A. Renz, J. Brack, A. Antibacterial materials. VI. Isolation and constitution of echinacoside, a glycoside from the roots of Echinacea angustifolia D.C. Helv. Chim. Acta, 1950, 33, 1877-1893.
2. Panizzi, L. Scarpati, M.L. Oriente, G. Chemical structure of oleuropein, bitter glucoside of olive with hypotensive activity. Gazz. Chim. Ital., 1966, 90, 1449-1485.
3. (a) Ragazzi, E. Veronesi, G. Ricerche sui costituenti idrosolubili delle olive I. Zuccheri e fenoli. Ann. Chim., 1967, 57, 1476-1486.
4. Montedoro, G. Servili, M. Baldioli, M. Miniati, E. Simple and hydrolizable phenolic compounds in virgin olive oil. 1. Their extraction, separation and quantitative and semiquantitative evaluation by HPLC. J. Agric. Food Chem., 1992, 40, 1571-1576.
5. Montedoro, G. Servili, M. Baldioli, M. Miniati, E. Simple and hydrolizable phenolic compounds in virgin olive oil. 2. Initial characterization of the hydrolizable fraction. J. Agric. Food Chem., 1992, 40, 1577-1580. (d) Montedoro, G. Servili, M. Baldioli, M. Selvaggini, R. Miniati, E. Macchioni, A. Simple and hydrolizable phenolic compounds in virgin olive oil. 3. Spectroscopic characterization of the secoiridoids derivatives. J. Agric. Food Chem., 1993, 41, 2228-2234.
6. Ryan, D. Antolovich, M. Prenzler, P. Robards, K. Lavee, S. Biotransformations of phenolic compounds in Olea europea L. Scientia Horticulturae, 2002, 92, 147-176.
7. Visioli, F. Galli, C. Olives and their production waste products as source of bioactive compounds. Curr. Top. Nutr. Res., 2003, 1, 85-88.
8. Bendini, A. Cerretani, L. Carrasco-Pancorbo, A. Gomez-Caravaca, A.M. Segura-Carretero, A. Fernandez-Gutierrez, A. Lercker, G. Phenolic molecules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical methods. An overview of the last decade. Molecules, 2007, 12, 1679-1719.
9. (a) Bonanome, A. Pagnan, A. Biffanti, S. Opportuno, A. Sorgato, F. Dorella, M. Maiorino, M. Ursini, F. Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification. Arterioscler. Thrombosis, 1986, 12, 529-533.
10. Grignaffini, P. Roma, P. Galli, C. Catapano, A. L. Protection of low-density lipoprotein from oxidation of 3,4-dihydroxyphenylethanol. Lancet, 1994, 343, 1296-1297.
11. Salami, M. Galli, C. De Angelis, L. Visioli, F. Pharmacol. Res. 1995, 31, 275-279 Carluccio, M.A.
12. Visioli, F. Galli, C. Natural antioxidants and prevention of coronary heart disease: the potential role of olive oil and its minor constituents. Nutr. Metabol. Cardiovasc. Dis. 1995, 5, 306-314.
13. Petroni, A. Balsevich, M. Salami, M. Papini, N. Montedoro, G.F. Galli, C. Inhibition of platelet aggregation and eicosanoid production by phenolic components of olive oil. Thromb. Res. 1995, 78, 151-160.
14. Hashimoto, T. Ibi, M. Matsuno, K. Nakashima, S. Tanigawa, T. Yoshikawa, T. Yabe-Nishimura, C. An endogenous metabolite of dopamine, 3,4- dihydroxyphenylethanol, acts as a unique cytoprotective agent against oxidative stress-induced injury. Free Radic. Bio. Med. 2004, 36, 555-564. (g) Nousis, L. Doulias, P. Aligiannis, N. Bazios, D. Agalias, A. Galaris, D. Mitakou, S. DNA protecting and genotoxic effects of olive oil related components in cells exposed to hydrogen peroxide. Free Radic. Res. 2005, 39, 787-795.
15. (a) Visioli, F. Galli, C. Oleuropein protects low density lipoprotein from oxidation. Life Sci., 1994, 55, 1965-1971.
16. Visioli, F. Caruso, D. Plasmati, D. Patelli, E. Mulinacci, R. Romani, A. Galli, C. Galli, G. Hydroxytyrosol, as a component o f olive mill waste water, is dose dependently absorbed and increases the antioxidant capacity o f rat plasma. Free Radic. Res. 2001, 34, 301-305.
17. Salami, M. Galli, C. De Angelis, L. Visioli, F. Formation of F2-isoprostanes in oxidized lowdensity lipoprotein: inhibitory effect of hydroxytyrosol. Pharmacol. Res., 1995, 31, 275-279.
18. Visioli, F. Galli, C. The effect of minor constituents of olive oil on cardiovascular disease: new findings. Nutr. Rew., 1998, 56, 142-147.
19. (a) Fabiani, R. De Bartolomeo, A. Rosignoli, P. Servili, M. Montedoro, G.F. Morozzi, G. Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Eur. J. Cancer Prev., 2002, 11, 351-358.
20. Fabiani, R. De Bartolomeo, A. Rosignoli, P. Servili, M. Selvaggini, R. Montedoro, G.F. Di Saverio, C. Morozzi, G. Virgin olive oil phenols inhibit proliferation of human promyelocytic leukemia cells (HL60) by inducing apoptosis and differentiation. J. Nutr., 2006, 136, 614-619.
21. Fabiani, R. Rosignoli, P. De Bartolomeo, A. Fuccelli, R. Morozzi, G. Inhibition of cell cycle progression by hydroxytyrosol is associated with upregulation of cyclin-dependent protein kinase inhibitors p21WAF1/Cip1 and p27Kip1 and with induction of differentiation in HL60 cells. J. Nutr., 2008, 138, 42-48.
22. Visioli, F. Bellomo, G. Galli, C. Free radical scavenging properties of olive oil polyphenols. Biochem. Biophys. Res. Commun., 1998, 247, 60-64.
23. (a) Manna, C. Galletti, P. Cucciolla, V. Montedoro, G. Zappia, V. Olive oil hydroxytyrosol protects human erythrocytes against oxidative damages. J. Nutr. Biochem., 1999, 10, 159-165.
24. Aruona, O.I. Deiana, M. Jenner, A. Halliwell, B. Harpakash, K. Banni, S. Corongiu, F.F. Dessi, M.A. Aeschbach, R. Effect of hydroxytyrosol found in extra virgin olive oil on oxidative DNA damage and on low-density lipoprotein oxidation. J. Agric. Food Chem., 1998, 46, 5181-5187.
25. Visioli, F. Galli, C. Plasmati, E. Viappiani, S. Hernandez, A. Colombo, C. Sala, A. Olive phenol hydroxytyrosol prevents passive smoking-induced oxidative stress. Circulation, 2000, 102, 2169-2171.
26. Bitler, C. Viale, T. M. Damai, B. Crea, R. Hydrolyzed olive vegetation water in mice has anti-inflammatory activity. J. Nutr., 2005, 135, 1475-1479.
27. (a) Bisignano, G. Tomaino, A. Lo Cascio, R. Crisafi, G. Uccella, N. Saija, A. On the in vitro antimicrobial activity of oleuropein and hydroxytyrosol. J. Pharm. Pharmacol., 1999, 51, 971-974.
28. Furneri, P. M. Piperno, A. Saija, A. Bisignano, G. Antimycoplasmal activity of hydroxytyrosol. Antimicrob. Agents Chemother., 2004, 48, 4892-4894.
29. Roig, A. Cayuela, M. L. Sanchez-Monedero, M. A. An overview on olive mill wastes and their valorisation methods. Waste Management, 2006, 26, 960-969.
30. (a) Capasso, R. Cristinzio, G. Evidente, A. Scognamiglio, F. Isolation, spectroscopy and selective phytotoxic effects of polyphenols from vegetable waste waters. Phytochemistry, 1992, 12, 4125-4128.
31. Della Greca, M. Monaco, P. Pinto, G. Pollio, A. Previtera, L. Temussi, F. Phytotoxicity of low-molecular-weight phenols from olive mill waste waters. Bull. Environ. Contam. Toxicol. 2001, 67, 352-359.
32. Fiorentino, A. Gentili, A. Isidori, A. Monaco, P. Nardelli, A. Parrella, A. Temussi, F. Environmental effects caused by olive oil mill wastewaters: toxicity comparison of low-molecularweight phenol components. J. Agric. Food Chem., 2003, 51, 1005-1009.
33. Rodis, P.S. Karathanos, V.T. Mantzavinou, A. Partitioning of olive oil antioxidants between oil and water phases. J. Agric. Food Chem., 2002, 50, 596-601.
34. Sabatini, N. Recent patents in olive oil industry: new technologies for the recovery of phenols compounds from olive oil, olive oil industrial byproducts and waste waters. Recent Pat. Food, Nutr. Agric., 2010, 2, 154-159.
35. (a) Crea, R. Method of obtaining a hydroxytyrosol-rich composition from vegetation water. US Patent 6,416,808.
36. Fernadez-Bolanos, G.J. Guillen, B.R. Rodriguez, A.R. Rodriguez, G.G. Heredia, M.A. Jimenez, A.A. Method for obtaining purified hydroxytyrosol from products and by-products derived from the olive tree. Patent WO02064537.
37. Villanova, L. Villanova, L. Fasiello, G. Merendino, A. Process for the recovery of tyrosol and hydroxytyrosol from oil mill waste-waters and catalytic oxidation method in order to convert tyrosol into hydroxytyrosol. US Patent 2006/0070953. (d) Pizzichini, M. Russo, C. Process for recovering the components of olive mill waste water with membrane technologies. Int. Patent WO2005123603. (e) Pizzichini, D. Russo, C. Vitagliano, M. Pizzichini, M. Romani, A. Ieri, F. Pinelli, P. Vignolini, P. Process for producing concentrated and refined actives from tissues and byproducts of Olea europea with membrane technologies. EP Patent 2,338,500A1.
38. Campo, M. Pinelli, P. Romani, A. HPLC/DAD/MS characterization and antioxidant activity of sweet chestnut (Castanea sativa M.) fractions. XXVI International Conference on Polyphenols, Florence, Italy, 22-25 July 2012 Vol.1, p.135-136.
39. Pizzichini, M. Romani, A. Pizzichini, D. Russo, C. Pinelli, P. Process for producing refined nutraceutic extracts from artichoke waste and from other plants of the Cynara genus. PCT/IT2008/000135.
40. Schopf C. Gottmann, G. Meisel, E.-M. Uber b-(3,4-dioxyphenyl)- Athylalkohol. Liebigs Ann. Chem., 1949, 563, 86-93.
41. Khafagy, E.Z. Lambooy J.P. Preparation of substituted phenethyl alcohols and a study of their bacteriostatic action in Escherichia coli B. J. Med. Chem., 1966, 9, 936-940.
42. Baraldi, P.G. Simoni, D. Manfredini, S. Menziani, E. Preparation of 3,4-dihydroxy-1-benzeneethanol: a reinvestigation. Liebigs Ann. Chem., 1983, 684-686.
43. Capasso, R. Evidente, A. Avollo, S. Solla, F. A highly convenient synthesis of hydroxytyrosol and its recovery from agricultural waste waters. J. Agric. Food Chem., 1999, 47, 1745-1748.
44. Tuck, K.L. Tan, H.-W. Hayball, P.J. Synthesis of tritium-labeled hydroxytyrosol, a phenolic compound found in olive oil. J. Agric. Food Chem., 2000, 48, 4087-4090.
45. Bianco, A. Passacantilli, P. Righi, G. Improved procedure for the reduction of esters to alcohols by sodium borohydride. Synth. Comm., 1988, 18, 1765-1771.
46. Bai, C. Yan, X. Takenaka, M. Sekiya, K. Nagata, T. Determination of synthetic hydroxytyrosol in rat plasma by GC-MS. J. Agric. Food Chem., 1998, 46, 3998-4001.
47. Espin, J.C. Soler-Rivas, C. Cantos, E. Tomas-Barberan, F. Wichers, H.J. Synthesis of the antioxidant hydroxytyrosol using tyrosinase as biocatalyst. J. Agric. Food Chem., 2001, 49, 1187-1193.
48. Guazzaroni, M. Crestini, C. Saladino, R. Layer-by-Layer coated tyrosinase: An efficient and selective synthesis of catechols. Bioorg. Med. Chem., 2012, 20, 157-166.
49. Allouche N. Sayadi, S. Synthesis of hydroxytyrosol, 2-hydroxytyrosol, 2-hydroxyphenylacetic acid and 3-hydroxyphenylacetic acid by differential conversion of tyrosol isomers using Serratia marcescens strain. J. Agric. Food Chem., 2005, 53, 6525-6530.
50. Bouallagui, Z. Sayadi, S. Production of high hydroxytyrosol via tyrosol conversion by Pseudomonas aeruginosa immobilized resting cells. J. Agric. Food Chem., 2006, 54, 9906-9911.
51. Hartmann, C. Meyer, V. Ueber jodobenzoesaure. Ber. Dtsch. Chem. Ges., 1893, 26, 1727-1732.
52. (a) Depernet, D. Francois, B. WO 02/057210 A1, PCT/FR02/00189, US 2002/0107416 Chem. Abstr., 2002, 137, 109123.
53. Ozanne, O. Pouysegu, L. Depernet, D. Francois, B. Quideau, S. A stabilized formulation of IBX (SIBX) for safe oxidation reactions including a new oxidative demethylation of phenolic methyl aryl ethers. Org. Lett., 2003, 5, 2903-2906.
54. Quideau, S. Chenede, A. Stabilized 2-Iodoxybenzoic Acid (SIBX). In: Encyclopedia of Reagents for Organic Synthesis (Online) John Wiley Sons Ltd., 2012, March 15, DOI: 10.1002/047084289X.rn01376.
55. Sorg, G. Mengel, A. Jung, G. Rademann, J. Oxidizing polymers: a polymer-supported, recyclable hypervalent iodine(V) reagent for the efficient conversion of alcohols, carbonyl compounds, and unsaturated carbamates in solution. Angew. Chem. -Int. Edit., 2001, 40, 4395-4397.
56. Bernini, R. Fabrizi, G. Pouysegu, L. Deffieux, D. Quideau, S. Synthesis of biologically active catecholic compounds via ortho-selective oxygenation of phenolic compounds using hypervalent iodine(V) reagents. Curr. Org. Synth., 2012, 9, 650-669.
57. De Lucia, M. Panzella, L. Pezzella, A. Napolitano, A. D'Ischia, M. Oxidative chemistry of the natural antioxidant hydroxytyrosol: hydrogen peroxidedependent hydroxylation and hydroquinone/o-quinone coupling pathways. Tetrahedron, 2006, 62, 1273-1278.
58. Pouysegu, L. Sylla, T. Garnier, T. Rojas, L.B. Charris, J. Deffieux, D. Quideau, S. Hypervalent iodine-mediated oxygenative phenol dearomatization reactions. Tetrahedron, 2010, 66, 5908-5917.
59. Bernini, R. Mincione, E. Crisante, F. Barontini, M. Fabrizi, G. A novel use of the recyclable polymer-supported IBX: an efficient chemoselective and regioselective oxidation of phenolic compounds. The case of hydroxytyrosol derivatives. Tetrahedron Lett., 2009, 50, 1307-1310.
60. (a) Bernini, R. Mincione, E. Barontini, M. Crisante, F. Convenient synthesis of hydroxytyrosol and its lipophilic derivatives from tyrosol or homovanillyl alcohol. J. Agric. Food Chem., 2008, 56, 8897-8904.
61. Bernini, R. Mincione, E. Barontini, M. Crisante, F. Procedimento per la preparazione di derivati dell'idrossitirosolo e di idrossitirosolo. IT Patent 0001381959, September 27, 2010.
62. Bernini, R. Mincione, E. Barontini, M. Crisante, F. Procedimento per la preparazione di derivati dell'idrossitirosolo e di idrossitirosolo via demetilazione ossidativa. IT Patent 0001382586, December 22, 2010.
63. Bernini, R. Cacchi, S. Fabrizi, G. Filisti, E. 2-Arylhydroxytyrosol derivatives via Suzuki-Miyaura cross-coupling. Org. Lett., 2008, 10, 3457-3460.
64. Azabou, S. Najjar, W. Ghorbel, A. Sayadi, S. Mild photochemical synthesis of the antioxidant hydroxytyrosol via conversion of tyrosol. J. Agric. Food Chem., 2007, 55, 4877-4882.
65. Bovicelli, P. Antonioletti, R. Mancini, S. Causio, S. Borioni, G. Ammendola, S. Barontini, M. Expedient synthesis of hydroxytyrosol and its esters. Synth. Commun., 2007, 37, 4245-4252.
66. Piersanti, G. Retini, M. Espartero, J.L. Madrona, A. Zappia, G. An efficient, economical synthesis of hydroxytyrosol and its protected forms via Baeyer-Villiger oxidation. Tetrahedron Lett., 2011, 52, 4938-4940.
67. Verhe, R. Papadoupolos, G. Boskou, D. Preparation of hydroxytyrosol. Bull. de Liaison -Groupe Polyphenols, 1992, 16, 237-244.
68. Zhang, Z.-Li Chen, J. Xu, Q. Rao, C. Qiao, C. Efficient synthesis of hydroxytyrosol from 3,4-dihydroxybenzaldehyde. Synth. Comm., 2012, 42, 794-798.
69. Gambacorta, A. Tofani, D. Bernini, R. Migliorini, D. High-yielding preparation of a stable precursor of hydroxytyrosol by total synthesis and from the natural glycoside oleuropein. J. Agric. Food Chem., 2007, 55, 3386-3391.
70. (a) Briante, R. La Cara, F. Tonziello, M. P. Febbraio, F. Nucci, R. Antioxidant activity of the main bioactive derivatives from oleuropein hydrolysis by hyperthermophilic -glycosidase. J. Agric. Food Chem., 2001, 49, 3198-3203.
71. Briante, R. La Cara, F. Febbraio, F. Patumi, M. Nucci, R. Bioactive derivatives from oleuropein by a biotransformations on Olea europea leaf extracts. J. Biotechnol., 2002, 93, 109-119.
72. Granados-Principal S. Quiles, J.L. Ramirez-Tortosa, C.L. Sanchez-Rovira, P. Ramirez-Tortosa, M.C. Hydroxytyrosol: from laboratory investigations to future clinical trials. Nutr. Rev., 2010, 68, 191-206.
73. Visioli, F. Bernardini, E. Extra virgin olive oil's polyphenols: biological activities. Curr. Pharm. Des., 2011, 17, 786-804.
74. Kang, N. Shin, S.H. Lee, H.J. Lee, K.W. Polyphenols as small molecular inhibitors of signaling cascades in carcinogenesis. Pharmacol. Ther., 2011, 130, 310-324.
75. Lee, K.W. Lee, H.J. The roles of polyphenols in cancer chemoprevention. Biofactors, 2006, 105-121.
76. Hanahan, D. Weinberg, R.A. The hallmarks of cancer. Cell., 2000, 100, 57-70.
77. Hanahan, D. Weinberg, R.A. Hallmarks of cancer: the next generation. Cell., 2011, 144, 646-674.
78. Cornwell, D.G. Ma, J. Nutritional benefit of olive oil: the biological effects of hydroxytyrosol and its arylating quinone adducts. J. Agric. Food. Chem., 2008, 56, 8774-8786.
79. Fabiani, R. Sepporta, M.V. Rosignoli, P. De Bartolomeo, A. Crescimanno, M. Morozzi G. Anti-proliferative and pro-Apoptotic activities of hydroxytyrosol on different tumour cells: the role of extracellular production of hydrogen peroxide. Eur. J. Nutr., 2012, 51, 455-464.
80. Visioli, F. Galli, C. Grande, S. Colonnelli, K. Patelli, C. Galli, G, Caruso, D. Hydroxytyrosol excretion differs between rats and humans and depends on the vehicle of administration. J. Nutr., 2003, 133, 1612-1615.
81. Gonzalez-Santiago, M, Fonolla, J, Lopez-Huertas, E. Human absorption of a supplement containing purified hydroxytyrosol, a natural antioxidant from olive oil, and evidence for its transient association with low-density lipoproteins. Pharmacol. Res., 2010, 61, 364-370.
82. Quiles, J.L. Farquharson, A.J. Simpson, D.K. Grant, I. Wahle, K.W. Olive oil phenolics: effects on DNA oxidation and redox enzyme mRNA in prostate cells. Br. J. Nutr., 2002, 88, 225-234.
83. Rizzo, A.M. Berselli, P. Zava, S. Montorfano, G. Negroni, M. Corsetto, P. Berra, B. Endogenous antioxidants and radical scavengers. Adv. Exp. Med. Biol., 2010, 698, 52-67.
84. Klaunig, J.E. Wang, Z. Pu, X. Zhou, S. Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol. Appl. Pharmacol., 2011, 254, 86-99.
85. Valko, M. Rhodes, C.J. Monocol, J. Izakovic, M. Mazur, M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact., 2006, 160, 1-40.
86. Palmer, H.J. Paulson, K.E. Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr. Rev., 1997, 55, 353-361.
87. Halliwell, B. Antioxidants in human health and disease. Ann. Rev. Nutr., 1996, 16, 33-50.
88. Grek, CL. Tew, K.D. Redox metabolism and malignancy. Curr. Opin. Pharmacol., 2010, 10, 362-368.
89. Nishikawa, M. Hyoudou, K. Kobayashi, Y. Umeyama, Y. Takakura, Y. Hashiba, M. Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes. J. Control. Release, 2005, 109, 101-107.
90. Klauning, E.L. Kamendulis, M. The role of oxidative stress in carcinogenesis. Annu. Rev. Pharmacol. Toxicol., 2004, 44, 239-267.
91. Storz, P. Reactive oxygen species in tumor progression. Front. Biosci., 2005, 10, 1881-1896.
92. Ziech, D. Franco, R. Pappa, A. Panayiotidis. M.I. Reactive oxygen species (ROS) induced genetic and epigenetic alterations in human carcinogenesis. Mutat. Res., 2011, 711, 167-173.
93. Shokolenko, I. Venediktova, N. Bochkareva, A. Wilson, G. L. Alexeyev M. F. Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res., 2009, 37, 2539-2548.
94. Campos, A.C.E. Molognoni, F. Melo, F.H.M. Galdier, L.C. Carneiro, C.R.W. D'Almeida, V. Correa, M. Jasiulionis, M. Oxidative stress modulate DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia, 2007, 9, 1111-1121.
95. Donkena, K.V. Young, C.Y. Tindall, D.J. Oxidative stress and DNA methylation in prostate cancer. Obstet. Gynecol. Int., 2010, 2010, 1-14.
96. Franco, R. Schoneveld, O. Georgakilas, A. Panayiotidis, M. Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett., 2008, 266, 6-11.
97. Lim, S.O. Gu, J.M. Kim, M.S. Kim, H.S. Park, Y.N. Park, C.K. Cho, J.W. Park, Y.M. Jung, G. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology, 2008, 135, 2128-2140.
98. Thannickal, V.J. Fanburg, B.L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell. Mol. Physiol., 2000, 279, L1005-L1028.
99. Karin, M. Nuclear factor-kB in cancer development and progression. Nature, 2006, 44, 431-436.
100. Bors, W. Michel, C. Chemistry of the antioxidant effect of polyphenols. Ann. N. Y. Acad. Sci., 2002, 957, 57-69.
101. Montero, A.J. Jassem, J. Cellular redox pathways as a therapeutic target in the treatment of cancer. Drugs, 2011, 71, 1385-1396.
102. O'Dowd, Y. Driss, F. Dang, P.M. Elbim, C. Gougerot-Pocidalo, M.A. Pasquier, C. El-Benna, J. Antioxidant effect of hydroxytyrosol, a polyphenol from olive oil: scavenging of hydrogen peroxide but not superoxide anion produced by human neutrophils. Biochem. Pharmacol., 2004, 68, 2003-2008.
103. Manna, C. Galletti, P. Cucciola, V. Montedoro, G.F. Zappia, V. Olive oil hydroxytyrosol protects human erythrocytes against oxidative damages. J. Nutr. Biochem., 1999, 10, 159-165.
104. Fabiani, R. Rosignoli, P. De Bartolomeo, A. Fuccelli, R. Servili, M. Montedoro, G.F. Morozzi, G. Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol and other olive phenolic compounds in human blood mononuclear cells and HL60 cells. J. Nutr. 2008, 138, 1411-1416.
105. Warleta, F. Quesada, C.S. Campos, M. Allouche, Y. Beltran, G. Gaforio, J.J. Hydroxytyrosol protect against oxidative DNA damage in human breast cells. Nutrients, 2011, 3, 839-857.
106. Salvini, S. Sera, F. Caruso, D. Giovannelli, L. Visioli, F. Saieva, C. Masala, G. Ceroti, M Giovacchini, V. Pitozzi, V. Galli, C. Romani, A. Mulinacci, N. Bortolomeazzi, R. Dolara, P. Palli, D. Daily consumption of a high phenol extra-virgin olive oil reduces oxidative DNA damage in postmenopausal women. Br. J. Nutr., 2006, 95, 742-751.
107. Guo, W. An, Y. Jiang, L. Geng, C. Zhong, L. The protective effects of hydroxytyrosol against UVB-induced DNA damage in HaCaT cells. Phytother. Res., 2010, 24, 352-359.
108. Manna, C. Galletti, P. Cucciola, V. Moltedo, O. Leone, A. Zappia, V. The protective effect of the olive oil polyphenol (3,4-dihydroxyphenyl)-ethanol counteracts reactive oxygen metabolite-induced cytotoxicity in Caco-2 cells. J. Nutr., 1997, 127, 286-292.
109. Nousis, L. Doulias, P.T. Aligiannis, N. Bazios, D. Agalias, A. Galaris, D. Mitakou, S. DNA protecting and genotoxic effects of olive oil related components in cells exposed to hydrogen peroxide. Free Radic. Res., 2005, 39, 787-795.
110. Dinkova-Kostova, A.T. Holtzclaw, W.D. Cole, R.N. Itoh, K. Wakabayashi, N. Katoh, Y. Yamamoto, M. Talalay, P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. USA, 2002, 99, 11908-11913.
111. Zhu, L. Liu, Z. Feng, Z. Hao, J. Shen, W. Li, X. Sun, L. Sharman, E. Wang, Y. Wertz, K. Weber, P. Shi, X. Liu, J. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J. Nutr. Biochem., 2010, 21, 1089-1098.
112. Zou, X. Feng, Z. Li, Y. Wang, Y. Wertz, K. Weber, P. Fu, Y. Liu, J. Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways. J. Nutr. Biochem., 2012, 23, 994-1006.
113. Bayram, B. Ozcelik, B. Grimm, S. Roeder, T. Schrader, C. Ernst, I.M. Wagner, A.E. Grune, T. Frank, J. Rimbach, G. A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. Rejuvenation. Res., 2012, 15, 71-81.
114. Massague, J. TGFbeta in cancer. Cell, 2008, 134, 215-230.
115. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer, 2003, 3, 11-22.
116. Vivanco, I. Sawyers, C.L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer, 2002, 2, 489-501.
117. Greenhough, A. Smartt, H.J.M. Moore, A.E. Roberts, H.R. Williams, A.C., Paraskeva, C., Kaidi, A. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the microenvironment. Carcinogenesis, 2009, 30, 377-386.
118. Green, D.R. Evan, G.I. A matter of life and death. Cancer Cell, 2002, 1, 19-30.
119. Danial, N.N. Korsmeyer, S.J. Cell death: critical control points. Cell, 2004, 116, 205-219.
120. Datta, S.R. Dudek, H. Tao, X. Masters, S. Fu, H. Gotoh, Y. Greenberg, M.E. Akt phosphorylation of BAD couples survival signals to the cellintrinsic death machinery. Cell., 1997, 91, 231-241.
121. Bonni, A. Brunet, A. West, A.E. Datta, S.R. Takasu, M.A. Greenberg, M.E. Cell survival promoted by the Ras-MAPK signaling pathway by transcription- dependent and -independent mechanisms. Science, 1999, 286, 1358-1362.
122. Della Ragione, F. Cucciolla, V. Borriello, A. Della Pietra V, Manna C, Galletti P, Zappia V. Pyrrolidine dithiocarbamate induces apoptosis by a cytochrome c-dependent mechanism. Biochem. Biophys. Res. Commun., 2000, 268, 942-946.
123. Della Ragione, F. Cucciolla, V. Criniti, V. Indaco, S. Borriello, A. Zappia, V. Antioxidants induce different phenotypes by a distinct modulation of signal transduction. FEBS Lett., 2002, 532, 289-294.
124. Fabiani, R. De Bartolomeo, A. Rosignoli, P. Servili, M. Montedoro, G.F. Morozzi, G. Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Eur. J. Cancer. Prev., 2002, 11, 351-358.
125. Fabiani, R. De Bartolomeo, A. Rosignoli, P. Servili, M. Selvaggini, R. Montedoro, G. F. Di Saverio, C. Morozzi, G. Virgin olive oil phenols inhibit proliferation of human promyelocytic leukemia cells (HL60) by inducing apoptosis and differentiation. J. Nutr., 2006, 136, 614-619.
126. Fabiani, R. Rosignoli, P. De Bartolomeo, A. Fuccelli, R. Morozzi, G. Inhibition of cell cycle progression by hydroxytyrosol is associated with upregulation of cyclin-dependent protein kinase inhibitors p21(WAF1/Cip1) and p27(Kip1) and with induction of differentiation in HL60 cells. J. Nutr., 2008,138, 42-48.
127. Fabiani, R. Fuccelli, R. Pieravanti, F. De Bartolomeo, A. Morozzi, G. Production of hydrogen peroxide is responsible for the induction of apoptosis by hydroxytyrosol on HL60 cells. Mol. Nutr. Food. Res., 2009, 53, 887-896.
128. Guichard, C. Pedruzzi, E. Fay, M. Marie, J.C. Braut-Boucher, F. Daniel, F. Grodet, A. Gougerot-Pocidalo, M.A. Chastre, E. Kotelevets, L. Lizard, G. Vandewalle, A. Driss, F. Ogier-Denis, E. Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis, 2006, 27, 1812-1827.
129. Notarincola, M. Pisanti, S. Tutino, V. Bocale, D. Rotelli M. T Gentile A. Memeo V. Bifulco M. Perri E. Caruso M. G. Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells. Genes. Nutr., 2011, 6, 63-69.
130. Corona, G. Deiana, M. Incani, A. Vauzour, D. Dessi, M.A. Spencer, J.P. HT inhibits proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1. Mol. Nutr. Food Res., 2009, 53, 897-903.
131. Bernini, R. Crisante, F. Merendino, N. Molinari, R. Soldatelli, M.C. Velotti, V. Synthesis of a novel ester of hydroxytyrosol and a-lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells. Eur. J. Med. Chem., 2011, 46, 439-446.
132. Han, J. Talorete, T. Yamada, P. Isoda, H. Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology, 2009, 59, 45-53.
133. Bouallagui, Z. Han, J. Isoda, H. Sayadi, S. Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food. Chem. Toxicol., 2011, 49, 179-184.
134. Sirianni, R. Chimento, A. De Luca, A. Casaburi, I. Rizza, P. Onofrio, A. Iacopetta, D. Puoci, F. Ando, S. Maggiolini, M. Pezzi. V. Oleuropein and HT inhibit MCF-7 breast cancer cell proliferation interfering with ERK1/2 activation. Mol. Nutr. Food Res., 2009, 53, 536-545.
135. Granados-Principal, S. Quiles, J. L. Ramirez-Tortosa, C. Camacho-Corencia, P. Sanchez-Rovira, P. Vera-Ramirez, L. Ramirez-Tortosa, MC. Hydroxytyrosol inhibits growth and cell proliferation and promotes high expression of sfrp4 in rat mammary tumours. Mol. Nutr. Food Res., 2011, 55, 117-126.
136. Menendez JA. Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (HerceptinTM) in HER2-overexpressing breast cancer cells. BMC Cancer, 2007, 7, 80-99.
137. Dunn, G.P. Bruce, A.T. Ikeda, H. Old. L.J. Schreiber, R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol., 2002, 3, 991-998.
138. Vesely, M. Kershaw, M.H. Schrieber, R.D. Smyth, M.J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol., 2011, 29, 235-271.
139. Ostrand-Rosenberg, S. Immune surveillance: a balance between pro-And anti-tumor immunity. Curr. Opin. Genet. Dev., 2008, 18, 11-18.
140. Coussens L. M. Werb, Z. Inflammation and cancer. Nature, 2002, 420, 860-867.
141. Grivennikov, S. I. Greten, F. R Karin, M. Immunity, inflammation and cancer. Cell, 2010, 140, 833-899.
142. Mantovani, A. Sozzani, S. Locati, M. Allavena, P. Sica, A. Macrophage polarization: tumor associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol., 2002, 23, 549-555.
143. Pollard, J. W. Tumor-educated macrophages promote tumor progression and metastasis. Nat. Rev. Cancer, 2004, 4, 71-78.
144. Murray, P.J. Wynn, T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Cancer, 2011, 11, 723-737.
145. Quian, B.Z. Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell, 2010, 141, 39-51.
146. Pages, F. Galon. J. Dieu-Nosjean, M.C. Tartour, E. Sautes-Fridman, C. Fridman, W.H. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene, 2010, 29, 1093-1102.
147. Mantovani, A. Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol., 2010, 22, 231-237.
148. Gabrilovich, D.I. Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol., 2009, 9, 162-174.
149. Richard, N. Arnold, S. Hoeller, U. Kilpert, C. Wertz, K. Schwager, J. Hydroxytyrosol is the major anti-inflammatory compound in aqueous olive extracts and impairs cytokine and chemokine production in macrophages. Planta Med., 2011, 77, 1890-1897.
150. Giner, E. Andujar. I. Recio, M.C. Rios, J.L Cerda-Nicolas, J.M. Giner, R.M. Oleuropein ameliorates acute colitis in mice. J. Agric. Food. Chem., 2011, 59, 12882-12892.
151. Zhang, X. Cao, J. Zhong, L. Hydroxytyrosol inhibits proinflammatory cytokines, iNOS, and COX-2 expression in human monocytic cells. Naunyn Schmiedebergs Arch. Pharmacol., 2009, 379, 581-586.
152. Balkwill, F. Tumor necrosis factor and cancer. Nat. Rev. Cancer, 2009, 9, 361-371.
153. Maiuri, M.C. De Stefano, D. Di Meglio, P. Irace, C. Savarese, M. Sacchi, R. Cinelli, M.P. Carnuccio, R. Hydroxytyrosol, a phenolic compound from virgin olive oil, prevents macrophage activation. Naunyn Schmiedebergs Arch. Pharmacol., 2005, 371, 457-465.
154. Zhang, X. Cao, J. Jiang, L. Zhong, L. Suppressive effects of hydroxytyrosol on oxidative stress and nuclear factor kappa B activation in THP-1 cells. Biol. Pharm. Bull., 2009, 32, 578-582.
155. Gong D, Geng C, Jiang L, Cao J, Yoshimura H, Zhong L.Effects of hydroxytyrosol-20 on carrageenan-induced acute inflammation and hyperalgesia in rats. Phytother. Res., 2009, 23, 646-650.
156. Sanchez-Fidalgo, S. Sanchez de Ibarguen, L. Cardeno, A. Alarcon de la Lastra C. Influence of extra virgin olive oil diet enriched with hydroxytyrosol in a chronic DSS colitis model. Eur. J. Nutr., 2012, 51, 497-506.