Antitumor Perspectives of Oleuropein and Its Metabolite Hydroxytyrosol: Recent Updates

Journal of Food Science

Volumn 83, Issue 7, 2018, Pages 1781-1791

  Imran, Muhammad ^a   Nadeem, Muhammad ^b   Gilani, Syed Amir ^a   Khan, Shaista ^c   Sajid, Muhammad Wasim ^b   Amir, Rai Muhammad ^d  

^a UNIVERSITY OF LAHORE   (Pakistan)

^b Department of Electrical Computer Engineering   (Pakistan)

^c Department of Zoology Shah Abdul University   (Pakistan)

^d PMAS ARID AGRICULTURE UNIVERSITY   (Pakistan)

Author keywords

anticancer perspectives; hydroxytyrosol; metabolism; oleuropein; olive oil phenols

Indexed keywords

3,4-DIHYDROXYPHENYLETHANOL; ANTINEOPLASTIC AGENT; ELENOLIC ACID; IRIDOID; OLEUROPEIN; OLIVE OIL; PHENETHYL ALCOHOL; PYRAN DERIVATIVE;

ANALOGS AND DERIVATIVES; ANIMAL; CELL MOTION; CELL PROLIFERATION; CHEMISTRY; CORONARY ARTERY DISEASE; DNA DAMAGE; DRUG EFFECT; HUMAN; NEOPLASM; NEOVASCULARIZATION (PATHOLOGY); OLIVE TREE; PREVENTION AND CONTROL; TUMOR INVASION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL MOVEMENT; CELL PROLIFERATION; CORONARY DISEASE; DNA DAMAGE; HUMANS; IRIDOIDS; NEOPLASM INVASIVENESS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; OLEA; OLIVE OIL; PHENYLETHYL ALCOHOL; PYRANS;

EID: 85049861308     PISSN: 00221147     EISSN: 17503841     Source Type: Journal    
DOI: 10.1111/1750-3841.14198     Document Type: Article

References (110)

1. Abaza, L., & Taamali, W. (2005). Natural antioxidant composition as correlated to stability of some Tunisian virgin olive oils. Rivista Italiano Delle Sostanze Gresse, 132, 12–18
2. Abaza, L., Talorete, T. P. N., Yamada, P., Kurita, Y., Zarrouk, M., & Isoda, H. (2007). Induction of growth inhibition and differentiation of human leukemia HL-60 cells by Tunisian Gerboui olive leaf extract. Bioscience, Biotechnology, and Biochemistry, 71, 1306–1312
3. Acquaviva, R., di Giacomo, C., Sorrenti, V., Galvano, F., Santangelo, R., Cardile, V., … Vanella, L. (2012). Antiproliferative effect of oleuropein in prostate cell lines. International Journal of Oncology, 41, 31–38
4. Al-Azzawie, H. F., & Alhamdani, M. S. S. (2006). Hypoglycemic and antioxidant effects of oleuropein in Alloxan-diabetic rabbits. Life Sciences, 78, 1371–1377
5. Allouche, A., & Jiménez, A. (2007). How heating affects extra virgin olive oil quality indexes and chemical composition. Journal of Agricultural and Food Chemistry, 55, 9646–9654
6. Amiot, M. J., Fleuriet, A., & Macheix, J. J. (1996). Importance and evolution of phenolic compounds in olive during growth and maturation. Journal of Agricultural and Food Chemistry, 34, 823–826
7. Artursson, P., & Karlsson, J. (1991). Correlation between oral-drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelian (Caco-2) cells. Biochemical and Biophysical Research Communications, 175, 880–885
8. Bai, C., Yan, X., Takenaka, M., Sekiya, S., & Nagata, T. (1998). Determination of synthetic hydroxytyrosol in rat plasma by GC-MS. Journal of Agricultural and Food Chemistry, 46, 3998–4001
9. Baraldi, P. G., Simoni, D., Manfredine, S., & Menziani, E. (1983). Preparation of 3,4-dihydroxy-1-benzeneethanol: A reinvestigation. Liebigs Annalen der Chemie, 83, 684–686
10. Barbaro, B., Toietta, G., Maggio, R., Arciello, M., Tarocchi, M., Galli, A., & Balsano, C. (2014). Effects of the olive derived polyphenol oleuropin on human health. IInternational Journal of Molecular Sciences, 15, 18508–18524
11. Bartoli, R., Fernandez Banares, F., Navarro, E., Castella, E., Mane, J., Alvarez, M., … Gassull, M. A. (2000). Effects of olive oil on early & late events of colon carcinogenesis in rats: Modulation of arachidoic acid metabolism and local prostaglandin E(2) synthesis. Gut, 46, 191–199
12. Benavente-Garcia, O., Castillo, J., Lorente, J., Ortuno, A., & Del Rio, J. A. (2000). Antioxidant activity of phenolics extracted from Olea europaea L. leaves. Food Chemistry, 68, 457–462
13. Boccio, P., & DiDeo, A. (2003). Liquid chromatography-tandem mass spectrometry analysis of oleuropein and its metabolite Hydroxytyrosol in rat plasma &urine after oral administration. Journal of Chromatography B, 785, 47–56
14. Budiyanto, A., Ahmed, N. U., Wu, A., Bito, T., Nikaido, O., Osawa, T., … Ichihashi, M. (2000). Protective effect of topically applied olive oil against photocar Hesperidin ogenesis following UVB exposure of mice. Carcinogenesis, 21, 2085–2090
15. Bulotta, S., Corradino, R., Celano, M., D'Agostino, M., Maiuolo, J., Oliverio, M., … Russo, D. (2011). Antiproliferative & anticancer effects on breast cancer cells of oleuropein and its semisynthetic preacetylated derivatives. Food Chemistry, 127, 1609–1614
16. Bulotta, S., Corradino, R., Celano, M., Maiuolo, J., D'Agostino, M., Oliverio, M., … Russo, D. (2013). Antioxidant and antigrowth action of peracetylated oleuropein in thyroid cancer cells. Journal of Molecular Endocrinology, 51, 181–189
17. Calderón-Montaño, J. M.1, Madrona, A., Burgos-Morón, E., Orta, M. L., Mateos, S., Espartero, J. L., & López-Lázaro, M. (2013). Selective cytotoxic activity of new lipophilic hydroxytyrosol alkyl ether derivatives. Journal of Agricultural and Food Chemistry, 61(21), 5046–5053
18. Cárdeno, A., Sánchez-Hidalgo, M., Cortes-Delgado, A., & Alarcón de la Lastra, C. (2013a). Mechanisms involved in the antiproliferative and proapoptotic effects of unsaponifiable fraction of extra virgin olive oil on HT-29 cancer cells. Nutrition and Cancer, 65, 908–918
19. Cárdeno, A1, Sánchez-Hidalgo, M., Rosillo, M. A., & Alarcón de la Lastra, C. (2013b). Oleuropein, a secoiridoid derived from olive tree, inhibits the proliferation of human colorectal cancer cell through downregulation of HIF-1α. Nutrition and Cancer, 65(1), 147–156
20. Chimento, A1, Casaburi, I., Rosano, C., Avena, P., De Luca, A., Campana, C., … Sirianni, R. (2014). Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. Molecular Nutrition & Food Research, 58(3), 478–489
21. Chu, J., Lloyd, F. L., Trifan, O. C., Knapp, B., & Rizzo, M. T. (2003). Potential involvement of cyclooxygenase-2 pathway in the regulation of tumor-associated angiogenesis and growth in pancreatic cancer. Molecular Cancer Therapeutics, 2, 1–7
22. Coccia, A., Bastianelli, D., Mosca, L., Monticolo, R., Panuccio, I., Carbone, A., … Lendaro, E. (2014). Extra virgin olive oil phenols suppress migration and invasion of T24 human bladder cancer cells through modulation of matrix metalloproteinase-2. Nutrition and Cancer, 66(6), 946–954
23. Cornwell, G. D., & Ma, J. (2008). Nutritional benefits of olive oil: The biological effects of hydroxytyrosol and its arylating quinone adducts. Journal of Agricultural and Food Chemistry, 56, 8774–8786
24. Corona, G., Deiana, M., Incani, A., Vauzour, D., Dessì, M. A., & Spencer, J. P. (2007). Inhibition of p38/CREB phosphorylation and COX-2 expression by olive oil polyphenols underlies their anti-proliferative effects. Biochemical and Biophysical Research Communications, 362, 606–611
25. Corona, G., Tzounis, X., Dessi, M. A., Deiana, M., Debnam, E. S., Visioli, F., & Spencer, J. P. E. (2006). The fate of olive oil polyphenols in the gastrointestinal tract: Implications of gastric and colonic microflora-dependent biotransformation. Free Radical Research, 40, 647–658
26. D'Angelo, S., Manna, C., Migliardi, V., Mazzoni, O., Morrica, P., Tuck, G. K. L., … Stupans, I. (2002). Structural characterisation of the metabolites of hydroxytyrosol, the principal phenolic component in olive oil, in rats. Journal of Agricultural and Food Chemistry, 50, 2404–2409
27. de la Torre-Carbot, K., Chávez-Servín, J. L., Jaúregui, O., Castellote, A. I., Lamuela-Raventós, R. M., Tarja, N., … López-Sabater, M. C. (2010). Elevated circulating LDL phenol levels in men who consumed virgin rather than refined olive oil are associated with less oxidation of plasma LDL. Journal of Nutrition, 140, 501–508
28. Di Francesco, A., Falconi, A., Di Germanio, C., Micioni Di Bonaventura, M. V., Costa, A., Caramuta, S., … D'Addario, C. (2015). Extravirgin olive oil up-regulates CB₁ tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms. Journal of Nutritional Biochemistry, 26(3), 250–258
29. Edgecombe, S. C., Stretch, G. L., & Hayball, P. J. (2000). OL, an antioxidant polyphenol from olive oil, is poorly absorbed from isolated perfused rat intestine. Journal of Nutrition, 130, 2996–3002
30. Elamin, M. H., Elmahi, A. B., Daghestani, M. H., Al-Olayan, E. M., Al-Ajmi, R. A., Alkhuriji, A. F., … Elkhadragy, M. F. (2017). Synergistic anti-breast-cancer effects of combined treatment with oleuropein and doxorubicin in vivo. Alternative Therapies in Health and Medicine, 23(7)
31. Espín, J. C., Soler-Rivas, C., Cantos, E., Tomás-Barberán, F. A., & Wichers, H. J. (2001). Synthesis of the antioxidant hydroxytyrosol using tyrosinase as biocatalyst. Journal of Agricultural and Food Chemistry, 49, 1187–1193
32. Fabiani, R., Bartolomeo, A., Rosignoli, P., Servili, M., Selvaggini, R., Montedoro, G. F., … Morozzi, G. (2006). Virgin olive oil phenols inhibit proliferation of human promyelocytic leukemia cells (HL60) by inducing apoptosis and differentiation. Journal of Nutrition, 136(3), 614–619
33. Fabiani, R., Rosignoli, P., De Bartolomeo, A., Fuccelli, R., & Morozzi, G. (2008a). 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. Journal of Nutrition, 138, 42–48
34. Fabiani, R., Rosignoli, P., De Bartolomeo, A., Fuccelli, R., Servili, M., Montedoro, G. F., & Morozzi, G. (2008b). Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol, and other phenolic compounds in human blood mononuclear cells and HL60 cells. Journal of Nutrition, 138, 1411–1416
35. Ferlay, J., Shin, H. R., Bray, F., Forman, D., & Mathers, C. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer, 15, 2893–2917
36. Fu, S., Arráez-Roman, D., Segura-Carretero, A., Menéndez, J. A., Menéndez-Gutiérrez, M. P., Micol, V., & Fernández-Gutiérrez, A. (2010). Qualitative screening of phenolic compounds in olive leaf extracts by hyphenated liquid chromatography and preliminary evaluation of cytotoxic activity against human breast cancer cells. Analytical and Bioanalytical Chemistry, 397(2), 643–654
37. Galeone, C., & Talamini, R. (2007). Fried foods, olive oil and colorectal cancer. Annals of Oncology, 18, 36–39
38. García-Villalba, R., Carrasco-Pancorbo, A., Oliveras-Ferraros, C., Vázquez-Martín, A., Menédez, J. A., Segura-Carretero, A., & Fernández-Gutiérrez, A. (2010). Characterization & quatification of phenolic compounds of extra-virgin olive oils with anticancer properties by a rapid & resolutive LC-ESI-TOF MS method. Journal of Pharmaceutical and Biomedical Analysis, 51, 416–429
39. Gikas, E., Papadoloulos, N., & Tsarbopoulos, A. (2006). Kinetic study of the acidic hydrolysis of oleuropeinthe major bioactive metabolite of olive oil. Journal of Liquid Chromatography & Related Technologies, 29, 497–508
40. Giordano, E., Davalos, A., Nicod, N., & Visioli, F. (2014). Hydroxytyrosol attenuates tunicamycin-induced endoplasmic reticulum stress in human hepatocarcinoma cells. Molecular Nutrition & Food Research, 58(5), 954–962
41. Gill, C. I. R., Boyd, A., McDermott, E., McCann, M., Servili, M., Selvaggini, R., … Rowland, I. (2005). Potential anti-cancer effects of virgin olive oil phenols on colorectal carcinogenesis models in vitro. International Journal of Cancer, 117, 1–7
42. Giner, E., Recio, M. C., Ríos, J. L., Cerdá-Nicolás, J. M., & Giner, R. M. (2016). Chemopreventive effect of oleuropein in colitis-associated colorectal cancer in c57bl/6 mice. Molecular Nutrition & Food Research, 60(2), 242–255
43. Goulas, V., Exarchou, V., Troganis, A. N., Psomiadou, E., Fotsis, T., Briasoulis, E., & Gerothanassis, I. P. (2009). Phytochemicals in olive-leaf extracts and their antiproliferative activity against cancer and endothelialcells. Molecular Nutrition & Food Research, 53, 600–608
44. Goya, L., Mateos, R., & Bravo, L. (2007). Effect of the olive oil phenol hydroxytyrosol on human hepatoma HepG2 cells. Protection against oxidative stress induced by tert-butylhydroperoxide. European Journal of Nutrition, 46(2), 70–78
45. Granados-Principal, S., El-Azem, N., Pamplona, R., Ramirez-Tortosa, C., Pulido-Moran, M., Vera-Ramirez, L., … Ramirez-Tortosa, M. 2014. Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochemical Pharmacology, 90(1):25–33
46. Hamadi, H. K., & Castellon, R. (2005). Oleuropein, a non toxic olive iridoid, is an anti-tumor agent and cytoskeleton disrupter. Biochemical and Biophysical Research Communications, 334, 769–778
47. Han, J., Talorete, T. P. N., Yamada, P., & Isoda, H. (2009). Anti-proliferative and apoptotic effects of oleuropein&hsydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology, 59, 45–53
48. Hashim, Y. Z. (2008). Inhibitory effects of olive oil on invasion in human colon adenocarcinoma cells in vitro. International Journal of Cancer, 122, 495–500
49. Hassan, Z. K., Elamin, M. H., Omer, S. A., Daghestani, M. H., Al-Olayan, E. S., Elobeid, M. A., & Virk, P. (2014). Oleuropein induces apoptosis via the p53 pathway in breast cancer cells. Asian Pacific Journal of Cancer Prevention, 14(11), 6739–6742
50. Hattori, Y., Nishigori, C., Tanaka, T., Uchida, K., Nikaido, O., Osawa, T., … Toyokuni, S. (1997). 8-Hydroxy-2%- deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure. Journal of Investigative Dermatology, 107, 733–737
51. Kang, S. N., Zhang, L., Huang, P. L., Chang, Y. T., & Huang, P. L. (2001). Capsaicin potentiates 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced differentiation of human promyelocytic leukemia HL-60 cells. European Journal of Pharmacology, 420, 83–90
52. Kimura, Y., & Sumiyoshi, M. (2009). Olive leaf extract and its main component oleuropein prevent chronic ultraviolet b radiation-induced skin damage and carcinogenesis in hairless mice. Journal of Nutrition, 139(11), 2079–2086
53. Lamy, S., Ben Saad, A., Zgheib, A., & Annabi, B. (2016). Olive oil compounds inhibit the paracrine regulation of TNF-α-induced endothelial cell migration through reduced glioblastoma cell cyclooxygenase-2 expression. Journal of Nutritional Biochemistry, 27, 136–145
54. Lamy, S., Ouanouki, A., Béliveau, R., & Desrosiers, R. R. (2014). Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation. Experimental Cell Research, 322(1), 89–98
55. Lee-Huang, S., Huang, P. L., Zhang, D., Lee, J. W., Bao, J., Sun, Y., … Huang, P. L. (2007). Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Fusion inhibition. Biochemical and Biophysical Research Communications, 354, 872–878
56. Lee-Huang, S., Zhang, L., Huang, P. L., & Chang, Y. T. (2003). Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. Biochemical and Biophysical Research Communications, 307, 1029–1037
57. Li, S., Han, Z., Ma, Y., Song, R., Pei, T., Zheng, T., … Liu, L. (2014). Hydroxytyrosol inhibits cholangiocarcinoma tumor growth: An in vivo and in vitro study. Oncology Reports, 31(1), 145–152
58. Llor, X., Pons, E., Roca, A., Alvarez, M., Mane, J., Fernandez Banares, F., & Gassull, M. A. (2003). The effects of fish oil, olive oil, oleic acid and linoleic acid on colorectal neoplastic processes. Clinical Nutrition, 22, 71–79
59. López, S., Pacheco, YM., Bermudez, B., Abia, R., Muriana, F. J. G. (2004). Olive oil and cancer. Grasas Aceites, 55, 33–41
60. Luo, C., Li, Y., Wang, H., Cui, Y., Feng, Z., Li, H., … Liu, J. (2013). Hydroxytyrosol promotes superoxide production and defects in autophagy leading to anti-proliferation and apoptosis on human prostate cancer cells. Current Cancer Drug Targets, 13(6), 625–639
61. Manna, C., & Galletti, P. (2000). Transport mechanism and metabolism of olive oil hydroxytyrosol in CaCO2 cells. FEBS Letters, 470, 341–344
62. Mao, W., Shi, H., Chen, X., Yin, Y., Yang, T., Ge, M., … Qian, X. (2012). Anti-proliferation and migration effects of oleuropein on human A549 lung carcinoma cells. Latin American Journal of Pharmacy, 32, 1217–1221
63. Menendez, J. A., Vazquez-Martin, A., Colomer, R., Brunet, J., Carrasco-Pancorbo, A., Garcia-Villalba, R., … Segura-Carretero, A. (2007). Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin) in HER2-overexpressing breast cancer cells. BMC Cancer, 7, 80
64. Menendez, J. A., Vazquez-Martin, A., Oliveras-Ferraros, C., Garcia-Villalba, R., Carrasco-Pancorbo, A., Fernandez-Gutierrez, A., & Segura-Carretero, A. (2008). Analyzing effects of extra-virgin olive oil polyphenols on breast cancer-associated fatty acid synthase protein expression using reverse-phase protein microarrays. International Journal of Molecular Medicine, 22(4), 433–439
65. Miro-Casas, E., Albadalego, M. F., Covas, M. I., Rodrigues, F. O., Colomer, E. M., Ravento's, R. M. L., & de la Torre Fornell, R. (2001a). Capillary gas chromatography-mass spectrometry quantitative determination of hydroxytyrosol and tyrosol in human urine after olive intake. Analytical Biochemistry, 294, 63–72
66. Miro-Casas, E., Albadalego, M. F., Pianells, M. I. C., Colomer, M. F., Ravento's, R. M. L., & de la Torre Fornell, R. (2001b). Tyrosol bioavailability in humans after ingestion of virgin olive oil. Clinical Chemistry, 47, 341–343
67. Miro-Casas, E., & Covas, M. (2003). HTl disposition in humans. Clinical Chemistry, 49(6), 945–952
68. Nazim, U. A., Ueda, M., Nikaido, O., Osawa, T., & Ichihashi, M. (1999). High levels of 8-hydroxy-2%-deoxyguanosine appear innormal human epidermis after a single dose of ultraviolet radiation. British Journal of Dermatology, 140, 226–231
69. Notarnicola, M., Pisanti, S., Tutino, V., Bocale, D., Rotelli, M.T., Gentile, A., … Caruso, M. G. (2011). Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells. Genes and Nutrition, 6, 63–69
70. Omar, S. H. (2008). Olive: Native of Mediterranean region and health benefits. Pharmacognosy Reviews, 2(3), 135–142
71. Omar, S. H. (2010). Cardioprotective and neuroprotective roles of oleuropein in olive oil. Saudi Pharmaceutical Journal, 18, 111–121
72. Owen, R. W. (1997). Fecal steroids & colorectal carcinogenesis. Scandinavian Journal of Gastroenterology, 222, 76–82
73. Owen, R. W., Giacosa, A., Hull, W. E., Haubner, R., Wurtele, G., Spiegelhalder, B., & Bartsch, H. (2000). Olive-oil consumption and health: The possible role of antioxidants. Lancet Oncology, 1, 107–112
74. Parzonko, A., Czerwińska, M. E., Kiss, A. K., & Naruszewicz, M. (2013). Oleuropein and oleacein may restore biological functions of endothelial progenitor cells impaired by angiotensin II via activation of Nrf2/heme oxygenase-1 pathway. Phytomedicine, 20, 1088–1094
75. Pereira, A. P., Ferreira, I. C. F.R., Marcelino, F., Valentao, P., Andrade, P. B., Seabra, R., … Pereira, J. A. (2007). Phenolic compounds and antimicrobial activity of Olive (Olea euroea L. Cv. Corbançosa) leaves. Molecules, 12, 1153–1162
76. Pinelli, P., & Galardi, C. (2003). Minor polar compound and fatty acid analysis in monocultivar virgin olive oils from Tuscany. Food Chemistry, 80, 331–336
77. Rigacci, S., Miceli, C1, Nediani, C., Berti, A., Cascella, R., Pantano, D., … Stefani, M. (2015). Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: A mechanistic insight. Oncotarget, 3,6(34), 35344–35357
78. Ronalli, A., Contento, S., Lucera, L., Di Febo, M., Marchegiani, D., & Di Fonzo, V. (2006). Factors affecting the content of iridoid oleuropein in olive leaves (Olea europea L.). Journal of Agricultural and Food Chemistry, 54, 434–440
79. Ryan, D., Antolovich, M., et al. (2002). Biotransformations of phenolic compounds in Olea europaea L. Scientia Horticulturae, 92, 147–176
80. Sarsour, E. H., Goswami, M., Kalen, A. L., Lafin, J. T., & Goswami, P. C. (2014). Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast-induced stimulation of breast cancer cell proliferation. Age (Dordr), 36(3), 9645
81. Sepporta, M. V., Fuccelli, R., Rosignoli, P., Ricci, G., Servili, M., & Fabiani, R. (2016). Oleuropein prevents azoxymethane-induced colon crypt dysplasia and leukocytes DNA damage in A/J mice. Journal of Medicinal Food. https://doi.org/10.1089/jmf.2016.0026
82. Sirianni, R., Chimento, A., De Luca, A., Casaburi, I., Rizza, P., Onofrio, A., … Pezzi, V. (2010). Oleuropein and hydroxytyrosol inhibit MCF-7 breast cancer cell proliferation interfering with ERK1/2 activation. Molecular Nutrition & Food Research, 54, 833–840
83. Smith, T. J., Yang, G. Y., Seril, D. N., Liao, J., & Kim, S. (1998). Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis by dietary olive oil and squalene. Carcinogenesis, 19(4), 703–706
84. Song, H., Lim, D. Y., Jung, J. I., Cho, H. J., Park, S. Y., Kwon, G. T., … Park, J. H. Y. (2017). Dietary oleuropein inhibits tumor angiogenesis and lymphangiogenesis in the B16F10 melanomaallograft model: A mechanism for the suppression of high-fat diet-induced solid tumor growth and lymph node metastasis. Oncotarget, 8(19), 32027–32042
85. Stark, A. H., Kossoy, G., Zusman, I., Yarden, G., & Madar, Z. (2003). Olive oil consumption during pregnancy and lactation in rats influences mammary cancer development in female offspring. Nutrition and Cancer, 46(1), 59–65
86. Stoneham, M., Goldacre, M., Seagroatt, V., & Gill, L. (2000). Olive oil, diet and colorectal cancer: An ecological study and a hypothesis. Journal of Epidemiology and Community Health, 54, 756–760
87. Sun, L., Luo, C., & Liu, J. (2014). Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food & Function, 5(8), 1909–1914
88. Takata, K. (1995). Glucose transporters in the transepithelial transport of glucose. Journal of Electron Microscopy, 45, 275–284
89. Tan, H. W., Tuck, K. L., et al. (2003). Simultaneous determination of oleuropein&hydroxytyrosol in rat plasma using liquidchromatography with fluorescence detection. Journal of Chromatography B, 785, 187–191
90. Terzouli, E., Donnini, S., Giachetti, A., Iñiguez, M. A., Fresno, M., Melillo, G., & Ziche, M. (2010). Inhibition of hypoxia inducible factor-1α by dihydroxyphenyletanol, a product from olive oil, blocks microsomal prostaglandin-E synthase-1/vascular endothelial growth factor expression and reduces tumor angiogenesis. Clinical Cancer Research, 16, 4207–4216
91. Terzuoli, E., Giachetti, A., Ziche, M., & Donnini, S. (2015). Hydroxytyrosol, a product from olive oil, reduces colon cancer growth by enhancing epidermal growth factor receptor degradation. Molecular Nutrition & Food Research, 60(3), 519–529
92. Thuy, N. T., & Takeuchi, H. (2001). Comparative effect of dietary olive, safflower, and linseed oils on spontaneous liver tumorigenesis in C3H/He mice. Journal of Nutritional Science and Vitaminology, 47(5), 363–366
93. Trifan, O. C., & Hla, T. (2003). Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis. Journal of Cellular and Molecular Medicine, 7, 207–222
94. Tuberoso, C. I., Kowalczyk, A., Sarritzu, E., & Cabras, P. (2007). Determination of antioxidant compounds and antioxidant activity in commercial oil seeds for food use. Food Chemistry, 103, 1494–1501
95. Tuck, K. L., & Hayball, P. J. (2002). Major phenolic compounds in olive oil: Metabolism and health effects. Journal of Nutritional Biochemistry, 13, 636–644
96. Tuck, K. L., Tan, H., & Hayball, P. J. (2000). Synthesis of tritiated hydroxytyrosol. Journal of Agricultural and Food Chemistry, 48, 4087–4090
97. Tutino, V., Caruso, M. G., Messa, C., Perri, E., & Notarnicola, M. (2012). Antiproliferative, antioxidant and anti-inflammatory effects of hydroxytyrosol on human hepatoma HepG2 and Hep3B cell lines. Anticancer Research, 32(12), 5371–5377
98. Verhe, R., Papadopoulos, G., & Boskou, D. (1992). Preparation of hydroxytyrosol. Bull. Liason-Groupe Polyphenols, 15, 237–244
99. Visioli, F., Bellomo, G., & Galli, C. (1998). Free radical-scavenging properties of olive oil polyphenols. Biochemical and Biophysical Research Communications, 247, 60–64
100. Visioli, F., Galli, C., Bornet, F., Mattei, A., Patelli, R., Galli, G., & Caruso, D. (2000a). Olive oil phenolics are dose-dependently absorbed in humans. FEBS Letters, 468, 159–160
101. Visioli, F., Galli, C., Plasmati, E., Viappiani, S., Hernandez, A., Colombo, C., & Sala, A. (2000b). Olive phenol hydroxytyrosol prevents passive smoking-induced oxidative stress. Circulation, 102, 2169–2171
102. Visioli, F., Poli, A., & Gall, C. (2002). Antioxidant and other biological activities of phenols fromolives and olive oil. Medicinal Research Reviews, 22, 65–75
103. Vissers, M. N., Zock, P. L., Roodenburg, A. J. C., Leenen, R., & Katan, M. B. (2002). Olive oil phenols are absorbed in humans. Journal of Nutrition, 139, 409–417
104. Vissers, M. N., Zock, P. L., & Katan, M. B. (2004). Bioavailability and antioxidant effects of olive oil phenols in humans: A review. European Journal of Clinical Nutrition, 58, 955–965
105. Warleta, F., Quesada, C. S., Campos, M., Allouche, Y., Beltrán, G., & Gaforio, J. J. (2011). Hydroxytyrosol protects against oxidative DNA damage in human breast cells. Nutrients, 3(10), 839–857
106. Yan, C. M., Chai, E. Q., Cai, H. Y., Miao, G. Y., & Ma, W. (2015). Oleuropein induces apoptosis via activation of caspases and suppression of phosphatidylinositol 3-kinase/protein kinase B pathway in HepG2 human hepatoma cell line. Molecular Medicine Reports, 11(6), 4617–4624
107. Yao, J., Wu, J., Yang, X., Yang, J., Zhang, Y., & Du, L. (2014). Oleuropein induced apoptosis in HeLa cells via a mitochondrial apoptotic cascade associated with activation of the c-Jun NH2-terminal kinase. Journal of Pharmacological Sciences, 125(3), 300–311
108. Zhao, B., Ma, Y., Xu, Z., Wang, J., Wang, F., Wang, D., … Jiang, H. (2014). Hydroxytyrosol, a natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. Cancer Letters, 347(1), 79–87
109. Zheng, A., Li, H., Xu, J., Cao, K., Li, H., Pu, W., … Feng, Z. (2015). Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: Role of AMP-activated protein kinase activation. British Journal of Nutrition, 113(11), 1667–1676
110. Zubair, H., Bhardwaj, A., Ahmad, A., Srivastava, S. K., Khan, M. A., Patel, G. K., … Singh, A. P. (2017). Hydroxytyrosol induces apoptosis and cell cycle arrest and suppresses multiple oncogenic signaling pathways in prostate cancer cells. Nutrition and Cancer, 69(6), 932–942