The Double-Edged Sword of Oleuropein in Ovarian Cancer Cells: From Antioxidant Functions to Cytotoxic Effects

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Jan 8

PMID 36614279

Authors

Stefania Scicchitano

Eleonora Vecchio

Anna Martina Battaglia

Manuela Oliverio

Monica Nardi

Antonio Procopio

Francesco Costanzo

Flavia Biamonte

Maria Concetta Faniello

Affiliations

Soon will be listed here.

Abstract

Oleuropein plays a key role as a pro-oxidant as well as an antioxidant in cancer. In this study, the activity of oleuropein, in an in vitro model of ovarian (OCCs) and breast cancer cells (BCCs) was investigated. Cell viability and cell death were analyzed. Oxidative stress was measured by CM-H2DCFDA flow cytometry assay. Mitochondrial dysfunction was evaluated based on mitochondrial reactive oxygen species (ROS) and GPX4 protein levels. Further, the effects on iron metabolism were analyzed by measuring the intracellular labile iron pool (LIP). We confirmed that high doses of oleuropein show anti-proliferative and pro-apoptotic activity on HEY and MCF-7 cells. Moreover, our results indicate that low doses of oleuropein impair cell viability without affecting the mortality of cells, and also decrease the LIP and ROS levels, keeping them unchanged in MCF-7 cells. For the first time, our data show that low doses of oleuropein reduce erastin-mediated cell death. Interestingly, oleuropein decreases the levels of intracellular ROS and LIP in OCCs treated with erastin. Noteworthily, we observed an increased amount of ROS scavenging enzyme GPX4 together with a consistent reduction in mitochondrial ROS, confirming a reduction in oxidative stress in this model.

Citing Articles

Phenolic extract from olive mill wastewater sustains mitochondrial bioenergetics upon oxidative insult.

Infantino I, Cubisino S, Conti Nibali S, Foti P, Tomasello M, Boninelli S Food Chem (Oxf). 2025; 10():100234.

PMID: 39791008 PMC: 11713508. DOI: 10.1016/j.fochms.2024.100234.

In Vitro Protective Effects of a Standardized Extract of (L.) Mill. Cladodes and L. Leaves Against Indomethacin-Induced Intestinal Epithelial Cell Injury.

Salamone F, Molonia M, Muscara C, Saija A, Cimino F, Speciale A Antioxidants (Basel). 2025; 13(12.

PMID: 39765835 PMC: 11673993. DOI: 10.3390/antiox13121507.

Ferroptosis and oral squamous cell carcinoma: connecting the dots to move forward.

Antonelli A, Battaglia A, Sacco A, Petriaggi L, Giorgio E, Barone S Front Oral Health. 2024; 5:1461022.

PMID: 39296524 PMC: 11408306. DOI: 10.3389/froh.2024.1461022.

Olive Leaves as a Source of Anticancer Compounds: In Vitro Evidence and Mechanisms.

Pessoa H, Zago L, Difonzo G, Pasqualone A, Caponio F, Costa D Molecules. 2024; 29(17).

PMID: 39275097 PMC: 11397062. DOI: 10.3390/molecules29174249.

The Role of Natural Products in Immunopharmacology.

Accardi G, Di Majo D, Aiello A Int J Mol Sci. 2024; 25(17).

PMID: 39273205 PMC: 11394681. DOI: 10.3390/ijms25179256.

References

Bulotta S, Corradino R, Celano M, Maiuolo J, DAgostino M, Oliverio M . Antioxidant and antigrowth action of peracetylated oleuropein in thyroid cancer cells. J Mol Endocrinol. 2013; 51(1):181-9. DOI: 10.1530/JME-12-0241. View

Benot-Dominguez R, Tupone M, Castelli V, dAngelo M, Benedetti E, Quintiliani M . Olive leaf extract impairs mitochondria by pro-oxidant activity in MDA-MB-231 and OVCAR-3 cancer cells. Biomed Pharmacother. 2020; 134:111139. DOI: 10.1016/j.biopha.2020.111139. View

Anter J, Fernandez-Bedmar Z, Villatoro-Pulido M, Demyda-Peyras S, Moreno-Millan M, Alonso-Moraga A . A pilot study on the DNA-protective, cytotoxic, and apoptosis-inducing properties of olive-leaf extracts. Mutat Res. 2011; 723(2):165-70. DOI: 10.1016/j.mrgentox.2011.05.005. View

Asgharzade S, Hashemi Sheikhshabani S, Ghasempour E, Heidari R, Rahmati S, Mohammadi M . The effect of oleuropein on apoptotic pathway regulators in breast cancer cells. Eur J Pharmacol. 2020; 886:173509. DOI: 10.1016/j.ejphar.2020.173509. View

cabarkapa A, Zivkovic L, Zukovec D, Djelic N, Bajic V, Dekanski D . Protective effect of dry olive leaf extract in adrenaline induced DNA damage evaluated using in vitro comet assay with human peripheral leukocytes. Toxicol In Vitro. 2014; 28(3):451-6. DOI: 10.1016/j.tiv.2013.12.014. View

Ali S, Davinelli S, Accardi G, Aiello A, Caruso C, Duro G . Healthy ageing and Mediterranean diet: A focus on hormetic phytochemicals. Mech Ageing Dev. 2021; 200:111592. DOI: 10.1016/j.mad.2021.111592. View

Li M, Wang X, Lu S, He C, Wang C, Wang L . Erastin triggers autophagic death of breast cancer cells by increasing intracellular iron levels. Oncol Lett. 2020; 20(4):57. PMC: 7418505. DOI: 10.3892/ol.2020.11918. View

Hashemi Sheikhshabani S, Amini-Farsani Z, Rahmati S, Jazaeri A, Mohammadi-Samani M, Asgharzade S . Oleuropein reduces cisplatin resistance in ovarian cancer by targeting apoptotic pathway regulators. Life Sci. 2021; 278:119525. DOI: 10.1016/j.lfs.2021.119525. View

Sottile R, Federico G, Garofalo C, Tallerico R, Faniello M, Quaresima B . Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition. Front Immunol. 2019; 10:224. PMC: 6404638. DOI: 10.3389/fimmu.2019.00224. View

10.

Leon-Gonzalez A, Auger C, Schini-Kerth V . Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy. Biochem Pharmacol. 2015; 98(3):371-80. DOI: 10.1016/j.bcp.2015.07.017. View

11.

Acquaviva R, Di Giacomo C, Sorrenti V, Galvano F, Santangelo R, Cardile V . Antiproliferative effect of oleuropein in prostate cell lines. Int J Oncol. 2012; 41(1):31-8. DOI: 10.3892/ijo.2012.1428. View

12.

Elamin M, Daghestani M, Omer S, Elobeid M, Virk P, Al-Olayan E . Olive oil oleuropein has anti-breast cancer properties with higher efficiency on ER-negative cells. Food Chem Toxicol. 2012; 53:310-6. DOI: 10.1016/j.fct.2012.12.009. View

13.

Lee W, Huang J, Shyur L . Phytoagents for cancer management: regulation of nucleic acid oxidation, ROS, and related mechanisms. Oxid Med Cell Longev. 2014; 2013:925804. PMC: 3886269. DOI: 10.1155/2013/925804. View

14.

Notarnicola M, Pisanti S, Tutino V, Bocale D, Rotelli M, Gentile A . Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells. Genes Nutr. 2011; 6(1):63-9. PMC: 3040798. DOI: 10.1007/s12263-010-0177-7. View

15.

Nardi M, Bonacci S, De Luca G, Maiuolo J, Oliverio M, Sindona G . Biomimetic synthesis and antioxidant evaluation of 3,4-DHPEA-EDA [2-(3,4-hydroxyphenyl) ethyl (3S,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate]. Food Chem. 2014; 162:89-93. DOI: 10.1016/j.foodchem.2014.04.015. View

16.

Scicchitano S, Giordano M, Lucchino V, Montalcini Y, Chiarella E, Aloisio A . The stem cell-associated transcription co-factor, ZNF521, interacts with GLI1 and GLI2 and enhances the activity of the Sonic hedgehog pathway. Cell Death Dis. 2019; 10(10):715. PMC: 6763495. DOI: 10.1038/s41419-019-1946-x. View

17.

Juli G, Oliverio M, Bellizzi D, Gallo Cantafio M, Grillone K, Passarino G . Anti-tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma. Cancers (Basel). 2019; 11(7). PMC: 6679356. DOI: 10.3390/cancers11070990. View

18.

Di Sanzo M, Cozzolino F, Battaglia A, Aversa I, Monaco V, Sacco A . Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration. Int J Mol Sci. 2022; 23(21). PMC: 9654362. DOI: 10.3390/ijms232112987. View

19.

Vecchio E, Fiume G, Mignogna C, Iaccino E, Mimmi S, Maisano D . IBTK Haploinsufficiency Affects the Tumor Microenvironment of Myc-Driven Lymphoma in E-myc Mice. Int J Mol Sci. 2020; 21(3). PMC: 7038122. DOI: 10.3390/ijms21030885. View

20.

Butt M, Tariq U, Iahtisham-Ul-Haq , Naz A, Rizwan M . Neuroprotective effects of oleuropein: Recent developments and contemporary research. J Food Biochem. 2021; 45(12):e13967. DOI: 10.1111/jfbc.13967. View