Anticancer, Anti-inflammatory, and Neuroprotective Effect of Oleocanthal from Virgin Olive Oil – A Review

Subasini Uthirapathy ¹*

This review highlights oleocanthal’s unique pharmacological properties, emphasizing its therapeutic potential in cancer, inflammation, Alzheimer's, and microbial infections.

Abstract

Background: Oleocanthal (OC), a phenolic compound found in extra virgin olive oil (EVOO), is renowned for its bioactive properties, including anti-inflammatory, anticancer, and neuroprotective effects. OC has been shown to inhibit the growth of various cancer cells, such as colon, breast, liver, and melanoma. Additionally, its potential role in neuroprotection, particularly in Alzheimer's disease, has been extensively researched. Methods: A comprehensive literature review was conducted to evaluate the pharmacokinetics, dynamics, and therapeutic mechanisms of OC. Databases such as PubMed, SCOPUS, and Web of Science were used to identify studies on OC’s therapeutic effects, particularly in cancer, Alzheimer's disease, inflammation, and microbial infections. Results: OC demonstrated potent anti-inflammatory effects by inhibiting cyclooxygenase (COX) enzymes and reducing pro-inflammatory signaling molecules. It also showed significant anticancer activity by modulating pathways like the apoptotic and HGF/c-Met pathways. In Alzheimer's disease, OC reduced astrocyte inflammation and promoted the clearance of amyloid beta proteins, supporting its neuroprotective role. Moreover, OC exhibited antimicrobial and antioxidant properties, further contributing to its therapeutic potential. Conclusion: Oleocanthal exhibits promising therapeutic effects across a range of diseases, including cancer and neurodegenerative disorders. However, while its in vitro pharmacological properties are well-established, further in vivo studies are needed to fully understand its potential as a medicinal agent. The findings of this review underscore OC’s potential to serve as a therapeutic lead molecule for a variety of conditions.

Keywords: Oleocanthal, cancer therapy, inflammation, Alzheimer's disease, extra virgin olive oil

References

A., Moore, R., Seibert, K. 2000. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res, 60, pp 1306–1311.

Abuznait, A.H., Qosa, H., Busnena, B.A., El Sayed, K.A. and Kaddoumi, A. 2013. Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies. ACS Chemical Neuroscience, 4(6), pp.973–982.

Abuznait, A.H.; Qosa, H.; O’Connell, N.D.; Akbarian-Tefaghi, J.; Sylvester, P.W.; El Sayed, K.A.; Kaddoumi, A. Induction of expression and functional activity of P-glycoprotein efflux transporter by bioactive plant natural products. Food Chem.Toxicol. 2011, 49, 2765–2772.

Akl, M.R., Ayoub, N.M., Mohyeldin, M.M., Busnena, B.A., Foudah, A.I., Liu, Y.-Y. and Sayed, K.A.E. 2014. Olive Phenolics as c-Met Inhibitors: (-)-Oleocanthal Attenuates Cell Proliferation, Invasiveness, and Tumor Growth in Breast Cancer Models. PLoS ONE, 9(5), p.e97622.

Andrewes, P., Busch, J., de Joode, T., Groenewegen, A., Alexandre, H. 2003.  Sensory properties of virgin olive oil polyphenols: Identification of deacetoxy-ligstroside aglycon as a key contributor to pungency. J. Agric. Food Chem, 51, pp 1415–1420.

Angeloni, C., Malaguti, M., Barbalace, M., and Hrelia, S. 2017. Bioactivity of Olive Oil Phenols in Neuroprotection. Ijms, 18 (11), pp 2230.

Beauchamp, G.K., Keast, R.S., Morel, D., Lin, J., Pika, J., Han Q., Lee, C.H., Smith, A.B., Breslin, P.A. 2005.  Phytochemistry: Ibuprofen-like activity in extra-virgin olive oil. Nature, 437, pp 45–46.

Boland, G., Butt, I., Prasad, R., Knox, W., Bundred, N., 2004.  COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ. Br. J. Cancer, 90, pp 423–429.

Cassiano, C.; Casapullo, A.; Tosco, A.; Monti, M.C.; Riccio, R. In cell interactome of oleocanthal, an extra virgin olive oil bioactive component. Nat. Prod. Commun. 2015, 10, 1013–1016.

Castejón M.L., Montoya T., Alarcón-De-La-Lastra C., Sánchez-Hidalgo M. Potential Protective Role Exerted by Secoiridoids from Olea europaea L. in Cancer, Cardiovascular, Neurodegenerative, Aging-Related, and Immunoinflammatory Diseases. Antioxidants. 2020; 9:149.

Cayan, H., and Erener, G. 2015. Effect of Olive Leaf (Olea Europaea) Powder on Laying Hens Performance, Egg Quality and Egg Yolk Cholesterol Levels. Asian Australas. J. Anim. Sc, 28 (4), pp 538–543.

Chin, K.Y., and Pang, K.L., 2017. Therapeutic Effects of Olive and Its Derivatives on Osteoarthritis: From Bench to Bedside. Nutrients, 9(10), p.1060.

Cicerale, S., Conlan, X.A., Barnett, N.W., Sinclair, A.J. and Keast, R.S.J. 2009. Influence of Heat on Biological Activity and Concentration of Oleocanthal a Natural Anti-inflammatory Agent in Virgin Olive Oil. Journal of Agricultural and Food Chemistry, 57(4), pp.1326–1330.

Cicerale, S., Lucas, L., and Keast, R. 2012. Antimicrobial, Antioxidant and Anti-inflammatory Phenolic Activities in Extra virgin Olive Oil. Curr. Opin. Biotechnol. 23 (2),  pp 129–135.

Cusimano, A.; Balasus, D.; Azzolina, A.; Augello, G.; Emma, M.R.; Di Sano, C.; Gramignoli, R.; Strom, S.C.; McCubrey, J.A.; Montalto, G.; et al. Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation. Int. J. Oncol. 2017, 51, 533–544.

De la Torre, R. Bioavailability of olive oil phenolic compounds in humans. Inflammopharmacology 2008, 16, 245–247.

De Paola, M., Sestito, S. E., Mariani, A., Memo, C., Fanelli, R., Freschi, M., et al. 2016. Synthetic and Natural Small Molecule TLR4 Antagonists Inhibit Motoneuron Death in Cultures from ALS Mouse Model. Pharmacol. Res, 103, pp 180–187.

Dick, L. 2018. The Prevention of Cardiovascular Disease through the Mediterranean Diet. J. Nutr. Edu. Behav, 50 (7), pp 53.

Diez-Bello, R., Jardin, I., Lopez, J.J., El Haouari, M., Ortega-Vidal, J., Altarejos, J., Salido, G.M., Salido, S and Rosado, J.A. 2019. (-) Oleocanthal inhibits proliferation and migration by modulating Ca2+ entry through TRPC6 in breast cancer cells. Biochimica Et Biophysica Acta. Molecular Cell Research, 1866(3), pp.474–485.

Fogli, S., Arena, C., Carpi, S., Polini, B., Bertini, S., Digiacomo, M., Gado, F., Saba, A., Saccomanni, G., Breschi, M.C., Nieri, P., Manera, C. and Macchia, M. 2016. Cytotoxic Activity of Oleocanthal Isolated from Virgin Olive Oil on Human Melanoma Cells. Nutrition and Cancer, 68(5), pp.873–877.

Fogliano, V., and Sacchi, R., 2006. Oleocanthal in olive oil: Between myth and reality. Molecular Nutrition & Food Research, 50(1), pp.5–6.

Francisco V, Ruiz-Fernández C, Lahera V, Lago F, Pino J, Skaltsounis L,González-Gay MA, Mobasheri A, Gómez R, Scotece M, Gualillo O. Natural Molecules for Healthy Lifestyles: Oleocanthal from Extra Virgin Olive Oil. J Agric Food Chem. 2019; 67:3845-3853

Gu, Y., Wang, J. and Peng, L. 2016a. (−)-Oleocanthal exerts anti-melanoma activities and inhibits STAT3 signaling pathway. Oncology Reports, 37(1), pp.483–491.

Han, C. Y., Koo, J. H., Kim, S. H., Gardenghi, S., Rivella, S., Strnad, P., and Kim, S. G. 2016. Hepcidin Inhibits Smad3 Phosphorylation in Hepatic Stellate Cells by Impeding Ferroportin-Mediated Regulation of Akt. Nat. Commun,  7 (1),pp  1–14.

Ilavenil, S., Karthik, D., Arasu, M. V., Vijayakumar, M., Srigopalram, S., Arokiyaraj, S., et al. (2015). Hepatoprotective Mechanism of Lycorine against Carbon Tetrachloride Induced Toxicity in Swiss Albino Mice - A Proteomic Approach. Asian Pac. J. Reprod. 4 (2), 123–128.

Kelly, R.R., McDonald, L.T., Jensen, N.R., Sidles, S.J. and LaRue, A.C., 2019. Impacts of Psychological Stress on Osteoporosis: Clinical Implications and Treatment Interactions. Frontiers in Psychiatry, 10(200), pp7-12

Khanal, P., Oh, W.K., Yun, H.J., Namgoong, G.M., Ahn, S.-G., Kwon, S.-M., Choi, H.K. and Choi, H.S. 2011. p-HPEA-EDA, a phenolic compound of virgin olive oil, activates AMP-activated protein kinase to inhibit carcinogenesis. Carcinogenesis, 32(4), pp.545–553.

Khanfar, M.A., Bardaweel, S.K., Akl, M.R. and El Sayed, K.A. 2015. Olive Oil-derived Oleocanthal as Potent Inhibitor of Mammalian Target of Rapamycin: Biological Evaluation and Molecular Modeling Studies. Phytotherapy Research, 29(11), pp.1776–1782.

LeGendre, O., Breslin, P.A. and Foster, D.A. 2015. (-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization. Molecular & Cellular Oncology, 2(4), p.e1006077.

Lozano-Castellón, J., López-Yerena, A., Rinaldi de Alvarenga, J.F., Romero Del Castillo-Alba, J., Vallverdú-Queralt, A., Escribano-Ferrer, E. and Lamuela-Raventós, R.M. 2020. Health-promoting properties of oleocanthal and oleacein: Two secoiridoids from extra-virgin olive oil. Critical Reviews in Food Science and Nutrition, 60(15), pp.2532–2548.

Maalej, A., Mahmoudi, A., Bouallagui, Z., Fki, I., Marrekchi, R. and Sayadi, S. 2017. Olive phenolic compounds attenuate deltamethrin-induced liver and kidney toxicity through regulating oxidative stress, inflammation and apoptosis. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 106(Pt A), pp.455–465.

Maher, P. 2017. Protective Effects of Fisetin and Other berry Flavonoids in Parkinson's Disease. Food Funct, 8, pp 3033–3042

Masferrer, J., Leahy, K., Koki, A., Zweifel, B., Settle, S., Woerner, B., Edwards, D., Flickinger,

Medina, E., Brenes, M., García, A., Romero, C. and de Castro, A. 2009. Bactericidal Activity of Glutaraldehyde-like Compounds from Olive Products. Journal of Food Protection, 72(12), pp.2611–2614.

Medina, E., de Castro, A., Romero, C. and Brenes, M. 2006. Comparison of the Concentrations of Phenolic Compounds in Olive Oils and Other Plant Oils:  Correlation with Antimicrobial Activity. Journal of Agricultural and Food Chemistry, 54(14), pp.4954–4961.

Mete M., Aydemir I., Unsal U.U., Collu F., Vatandas G., Gurcu B., Duransoy Y.K., Taneli F., Tuglu M.I., Selcuki M. Neuroprotective effects of oleocanthal, a compound in virgin olive oil, in a rat model of traumatic brain injury. Turk. Neurosurg. 2017; 28:858–865.

Mohyeldin, M.M.; Busnena, B.A.; Akl, M.R.; Dragoi, A.M.; Cardelli, J.A.; El Sayed, K.A. Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer. Eur. J. Med. Chem. 2016, 118, 299–315.

Momtaz, S., Niaz, K., Maqbool, F., Abdollahi, M., Rastrelli, L. and Nabavi, S.M. 2016. STAT3 targeting by polyphenols: Novel therapeutic strategy for melanoma. BioFactors, 43(3), pp.347–370.

Monti, M.C., Margarucci, L., Tosco, A., Riccio, R. and Casapullo, A. 2011. New insights on the interaction mechanism between tau protein and oleocanthal, an extra-virgin olive-oil bioactive component. Food & Function, 2(7), pp.423–428.

Ortiz, M., Soto-Alarcón, S. A., Orellana, P., Espinosa, A., Campos, C., López-Arana, S., et al. 2020. Suppression of High-Fat Diet-Induced Obesity-Associated Liver Mitochondrial Dysfunction by Docosahexaenoic Acid and Hydroxytyrosol Co-administration. Dig. Liver Dis, 52 (8), pp 895–904.

Pang K.-L., Chin K.-Y. The Biological Activities of Oleocanthal from a Molecular Perspective. Nutrients. 2018; 10:570.

Pei, T., Meng, Q., Han, J., Sun, H., Li, L., Song, R., Sun, B., Pan, S., Liang, D. and Liu, L. 2016. (-)-Oleocanthal inhibits growth and metastasis by blocking activation of STAT3 in human hepatocellular carcinoma. Oncotarget, [online] 7(28), pp.43475–43491.

Peyrot des Gachons, C., Uchida, K., Bryant, B., Shima, A., Sperry, J.B., Dankulich-Nagrudny, L., Tominaga, M., Smith, A.B., Beauchamp, G.K., Breslin, P.A. 2011.  Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J. Neurosci., 31, pp 999–1009.

Pirozzi, C., Lama, A., Simeoli, R., Paciello, O., Pagano, T. B., Mollica, M. P., et al. 2016. Hydroxytyrosol Prevents Metabolic Impairment Reducing Hepatic Inflammation and Restoring Duodenal Integrity in a Rat Model of NAFLD. J. Nutr. Biochem, 30, pp 108–115.

Pitt, J., Roth, W., Lacor, P., Smith, A.B., Blankenship, M., Velasco, P., De Felice, F., Breslin, P. and Klein, W.L. 2009. Alzheimer’s-associated Aβ oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicology and Applied Pharmacology, 240(2), pp.189–197.

Polini B., Digiacomo M., Carpi S., Bertini S., Gado F., Saccomanni G., Macchia M., Nieri P., Manera C., Fogli S. Oleocanthal and oleacein contribute to the in vitro therapeutic potential of extra virgin oil-derived extracts in non-melanoma skin cancer. Toxicol. In Vitro. 2018; 52:243–250.

Ritchason, J. 2000. Olive Leaf Extract-Potent Antimicrobial, Antiviral and Antifungal Agent. Australia: Woodland Publishing.

Romero, C., Medina, E., Vargas, J., Brenes, M. and De Castro, A. 2007. In vitro activity of olive oil polyphenols against Helicobacter pylori. Journal of agricultural and food chemistry, 55(3), pp.680–6.

Rosignoli P., Fuccelli R., Fabiani R., Servili M., Morozzi G. Effect of olive oil phenols on the production of inflammatory mediators in freshly isolated human monocytes. J. Nutr. Biochem. 2013; 24:1513–1519.

Saeed, M., Arain, M. A., Ali Fazlani, S., Marghazani, I. B., Umar, M., Soomro, J., et al. 2021. A Comprehensive Review on the Health Benefits and Nutritional Significance of Fucoidan Polysaccharide Derived from Brown Seaweeds in Human, Animals and Aquatic Organisms. Aquacult. Nutr, 27, pp 633-654.‏

Saleem, T. M., Chetty, C. M., Ramkanth, S. V. S. T., Rajan, V. S. T., Kumar, K. M., and Gauthaman, K. 2010. Hepatoprotective Herbs–A Review. Int. J. Res. Pharm. Sci. 1 (1), 1–5.

Sarrafchi, A., Bahmani, M., Shirzad, H., and Rafieian-Kopaei, M. 2016. Oxidative Stress and Parkinson's Disease: New Hopes in Treatment with Herbal Antioxidants. Curr. Pharm. Des, 22, pp 238–246.

Scotece M., Gomez R., Conde J., Lopez V., Gomez-Reino J., Lago F., Smith A.S., III, Gualillo O. Oleocanthal Inhibits Proliferation and MIP-1α Expression in Human Multiple Myeloma Cells. Curr. Med. Chem. 2013; 20:2467–2475.

Scotece, M., Gómez, R., Conde, J., Lopez, V., Gómez-Reino, J.J., Lago, F., Smith, A.B. and Gualillo, O. 2012. Further evidence for the anti-inflammatory activity of oleocanthal: Inhibition of MIP-1α and IL-6 in J774 macrophages and in ATDC5 chondrocytes. Life Sciences, 91(23-24), pp.1229–1235.

Siddique, A.B., Kilgore, P.C.S.R., Tajmim, A., Singh, S.S., Meyer, S.A., Jois, S.D., Cvek, U., Trutschl, M. and Sayed, K.A.E. 2020. (−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer. Nutrients, 12(6), p.1749.

Smith, A.B., Han, Q., Breslin, P.A.S. and Beauchamp, G.K. 2005. Synthesis and Assignment of Absolute Configuration of (−)-Oleocanthal:  A Potent, Naturally Occurring Non-Steroidal Anti-inflammatory and Anti-oxidant Agent Derived from Extra Virgin Olive Oils. Organic Letters, 7(22), pp.5075–5078.

Smith, A.B., Sperry, J.B. and Han, Q. 2007. Syntheses of (−)-Oleocanthal, a Natural NSAID Found in Extra Virgin Olive Oil, the (−)-Deacetoxy-Oleuropein Aglycone, and Related Analogues. The Journal of Organic Chemistry, 72(18), pp.6891–6900.

Techathuvanan, C., Reyes, F., David, J.R.D., and Davidson, P.M. 2014. Efficacy of Commercial Natural Antimicrobials Alone and in Combinations against Pathogenic and Spoilage Microorganisms. Journal of Food Protection, 77(2), pp.269–275.

Thirumalai, T., David, E., Therasa, S. V., and Elumalai, E. 2011. Restorative Effect of Eclipta alba in CCl4 Induced Hepatotoxicity in Male Albino Rats. Asian Pac. J. Trop. Dis. 1 (4), pp304–307.

Yang Y., Zhang X., Xu M., Wu X., Zhao F., Zhao C. Quercetin attenuates collagen-induced arthritis by restoration of Th17/Treg balance and activation of Heme Oxygenase 1-mediated anti-inflammatory effect. Int. Immunopharmacol. 2018; 54:153–162.

Zbakh, H., and El Abbassi, A. 2012. Potential Use of Olive Mill Wastewater in the Preparation of Functional Beverages: A Review. J. Funct. Foods, 4, pp 53–65.

Zhang, Y., and Zheng, X.F.S. 2012. mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors. Cell Cycle, 11(3), pp.594–603.