Recent evidences indicates that hydroxytyrosol, one of the main olive oil phenols, possess antitumor effects because of its pro-oxidant properties and the capacity to inhibit proliferation and to promote apoptosis in several tumor cell lines, although most of the results were obtained for breast and digestive systems cancers.
In this study, we evaluated the activities of hydroxytyrosol against papillary (TPC-1, FB-2) and follicular (WRO) thyroid cancer cell lines.
Cellular viability revealed that high doses of hydroxytyrosol reduced cancer cells viability concomitantly with a reduction of cyclin D1 expression and an up-regulation of cell cycle key modulator p21 levels. In the same experimental conditions, Annexin V–PI staining and DNA laddering revealed that hydroxytyrosol exerts proapoptotic effects on papillary and follicular cancer cells. Furthermore, by Western blot analysis, we observed that hydroxytyrosol treatment reduced thyroid cancer cells viability by promoting apoptotic cell death via intrinsic pathway.
Collectively, our results demonstrated for the first time that in thyroid cancer cells hydroxytyrosol promoted apoptosis at higher doses with respect to other cancer cells lines. Therefore, further studies will reveal the mechanisms by which thyroid cancer cells are more resistant to the proapoptotic effect exerted by hydroxytyrosol as well as the potential application as novel target therapeutic in thyroid cancer.
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Buckland G, Gonzalez CA (2015) The role of olive oil in disease prevention: a focus on the recent epidemiological evidence from cohort studies and dietary intervention trials. Br J Nutr 113(Suppl 2):S94–S101. doi:10.1017/s0007114514003936
Keys A (1995) Mediterranean diet and public health: personal reflections. Am J Clin Nutr 61(6 Suppl):1321s–1323s
Psaltopoulou T, Kosti RI, Haidopoulos D, Dimopoulos M, Panagiotakos DB (2011) Olive oil intake is inversely related to cancer prevalence: a systematic review and a meta-analysis of 13,800 patients and 23,340 controls in 19 observational studies. Lipids Health Dis 10:127. doi:10.1186/1476-511x-10-127
Casaburi I, Puoci F, Chimento A, Sirianni R, Ruggiero C, Avena P et al (2013) Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies. Mol Nutr Food Res 57(1):71–83. doi:10.1002/mnfr.201200503
Bermudez B, Lopez S, Ortega A, Varela LM, Pacheco YM, Abia R et al (2011) Oleic acid in olive oil: from a metabolic framework toward a clinical perspective. Curr Pharm Des 17(8):831–843
Fini L, Hotchkiss E, Fogliano V, Graziani G, Romano M, De Vol EB et al (2008) Chemopreventive properties of pinoresinol-rich olive oil involve a selective activation of the ATM-p53 cascade in colon cancer cell lines. Carcinogenesis 29(1):139–146. doi:10.1093/carcin/bgm255
Rafehi H, Ververis K, Karagiannis TC (2012) Mechanisms of action of phenolic compounds in olive. J Diet Suppl 9(2):96–109. doi:10.3109/19390211.2012.682644
Servili M, Esposto S, Fabiani R, Urbani S, Taticchi A, Mariucci F et al (2009) Phenolic compounds in olive oil: antioxidant, health and organoleptic activities according to their chemical structure. Inflammopharmacology 17(2):76–84. doi:10.1007/s10787-008-8014-y
Della Ragione F, Cucciolla V, Borriello A, Della Pietra V, Manna C, Galletti P et al (2000) Pyrrolidine dithiocarbamate induces apoptosis by a cytochrome c-dependent mechanism. Biochem Biophys Res Commun 268(3):942–946. doi:10.1006/bbrc.2000.2161
Fabiani R, Fuccelli R, Pieravanti F, De Bartolomeo A, Morozzi G (2009) Production of hydrogen peroxide is responsible for the induction of apoptosis by hydroxytyrosol on HL60 cells. Mol Nutr Food Res 53(7):887–896. doi:10.1002/mnfr.200800376
Fabiani R, Sepporta MV, Rosignoli P, De Bartolomeo A, Crescimanno M, Morozzi G (2012) Anti-proliferative and pro-apoptotic activities of hydroxytyrosol on different tumour cells: the role of extracellular production of hydrogen peroxide. Eur J Nutr 51(4):455–464. doi:10.1007/s00394-011-0230-3
Rosignoli P, Fuccelli R, Sepporta MV, Fabiani R (2016) In vitro chemo-preventive activities of hydroxytyrosol: the main phenolic compound present in extra-virgin olive oil. Food Funct 7(1):301–307. doi:10.1039/c5fo00932d
Sipos JA, Mazzaferri EL (2010) Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol) 22(6):395–404. doi:10.1016/j.clon.2010.05.004
Altekruse S, Das A, Cho H, Petkov V, Yu M (2015) Do US thyroid cancer incidence rates increase with socioeconomic status among people with health insurance? An observational study using SEER population-based data. BMJ Open 5(12):e009843. doi:10.1136/bmjopen-2015-009843
Sherman SI (2003) Thyroid carcinoma. Lancet 361(9356):501–511
Bulotta S, Corradino R, Celano M, Maiuolo J, D’Agostino M, Oliverio M et al (2013) Antioxidant and antigrowth action of peracetylated oleuropein in thyroid cancer cells. J Mol Endocrinol 51(1):181–189. doi:10.1530/jme-12-0241
Basolo F, Giannini R, Toniolo A, Casalone R, Nikiforova M, Pacini F et al (2002) Establishment of a non-tumorigenic papillary thyroid cell line (FB-2) carrying the RET/PTC1 rearrangement. Int J Cancer 97(5):608–614
Arturi F, Russo D, Bidart JM, Scarpelli D, Schlumberger M, Filetti S (2001) Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors. Eur J Endocrinol 145(2):129–135
Vizza D, Perri A, Lofaro D, Toteda G, Lupinacci S, Leone F et al (2013) Exposure to nerve growth factor worsens nephrotoxic effect induced by Cyclosporine A in HK-2 cells. PLoS One 8(11):e80113. doi:10.1371/journal.pone.0080113
Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Morozzi G (2008) 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 138(1):42–48
Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Servili M, Montedoro GF et al (2008) 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 138(8):1411–1416
Bouallagui Z, Han J, Isoda H, Sayadi S (2011) Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food Chem Toxicol 49(1):179–184. doi:10.1016/j.fct.2010.10.014
Fabiani R, De Bartolomeo A, Rosignoli P, Servili M, Montedoro GF, Morozzi G (2002) Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Eur J Cancer Prev 11(4):351–358
Guichard C, Pedruzzi E, Fay M, Marie JC, Braut-Boucher F, Daniel F et al (2006) Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis 27(9):1812–1827. doi:10.1093/carcin/bgl009
Sirianni R, Chimento A, De Luca A, Casaburi I, Rizza P, Onofrio A et al (2010) Oleuropein and hydroxytyrosol inhibit MCF-7 breast cancer cell proliferation interfering with ERK1/2 activation. Mol Nutr Food Res 54(6):833–840. doi:10.1002/mnfr.200900111
Terzuoli E, Donnini S, Giachetti A, Iniguez MA, Fresno M, Melillo G et al (2010) Inhibition of hypoxia inducible factor-1alpha by dihydroxyphenylethanol, a product from olive oil, blocks microsomal prostaglandin-E synthase-1/vascular endothelial growth factor expression and reduces tumor angiogenesis. Clin Cancer Res 16(16):4207–4216. doi:10.1158/1078-0432.ccr-10-0156
Knauf JA, Fagin JA (2009) Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug targets. Curr Opin Cell Biol 21(2):296–303. doi:10.1016/j.ceb.2009.01.013
Ribeiro FR, Meireles AM, Rocha AS, Teixeira MR (2008) Conventional and molecular cytogenetics of human non-medullary thyroid carcinoma: characterization of eight cell line models and review of the literature on clinical samples. BMC Cancer 8:371. doi:10.1186/1471-2407-8-371
Schweppe RE, Klopper JP, Korch C, Pugazhenthi U, Benezra M, Knauf JA et al (2008) Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab 93(11):4331–4341. doi:10.1210/jc.2008-1102
D’Archivio M, Santangelo C, Scazzocchio B, Vari R, Filesi C, Masella R et al (2008) Modulatory effects of polyphenols on apoptosis induction: relevance for cancer prevention. Int J Mol Sci 9(3):213–228
Floyd DH, Zhang Y, Dey BK, Kefas B, Breit H, Marks K et al (2014) Novel anti-apoptotic microRNAs 582-5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim. PLoS One 9(5):e96239. doi:10.1371/journal.pone.0096239
Wyllie AH (2010) “Where, O death, is thy sting?” A brief review of apoptosis biology. Mol Neurobiol 42(1):4–9. doi:10.1007/s12035-010-8125-5
Chimento A, Casaburi I, Rosano C, Avena P, De Luca A, Campana C et al (2014) Oleuropein and hydroxytyrosol activate GPER/GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. Mol Nutr Food Res 58(3):478–489. doi:10.1002/mnfr.201300323
Corona G, Deiana M, Incani A, Vauzour D, Dessi MA, Spencer JP (2009) Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1. Mol Nutr Food Res 53(7):897–903. doi:10.1002/mnfr.200800269
Covas MI, de la Torre K, Farre-Albaladejo M, Kaikkonen J, Fito M, Lopez-Sabater C et al (2006) Postprandial LDL phenolic content and LDL oxidation are modulated by olive oil phenolic compounds in humans. Free Radic Biol Med 40(4):608–616. doi:10.1016/j.freeradbiomed.2005.09.027
We thank Dr. Sabrina Bossio, Biotechnology Research Unit, ASP Cosenza, Aprigliano, Italy, for help with Annexin V–PI assay.
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study informed consent is not required.
G. Toteda and S. Lupinacci have contributed equally to this work.
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Toteda, G., Lupinacci, S., Vizza, D. et al. High doses of hydroxytyrosol induce apoptosis in papillary and follicular thyroid cancer cells. J Endocrinol Invest 40, 153–162 (2017). https://doi.org/10.1007/s40618-016-0537-2
- Thyroid cancer
- Olive oil