Importance of phenolic compounds in virgin olive oil in cancer treatment

Cancer is a leading cause of mortality worldwide. A primary challenge in cancer therapeutics is that of the transformation of aggressive tumours into chronic illnesses [9]. Over the years, research in this field has evolved, and therapy currently extends beyond conventional treatments such as radiotherapy, chemotherapy, and surgical removal [10]. The escalating cancer rates highlight the crucial need to explore natural compounds for treatment that present themselves as an interesting option for prevention or in conjunction with pharmacological or conventional therapies [9,10]. Furthermore, the usage of natural products is a fundamental approach since they present accessibility and reduced cytotoxicity [10]. These compounds can originate from plants, animals, marine organisms, or microorganisms, and they target molecules found both in normal and tumour cells or molecules that only appear in cancer cell pathways [11,12].

Most drugs used in cancer treatment are only approved for adults as paediatric cancers are a limited area for investment [12]. However, several natural compounds have been the subject of research, specifically for NB [13]. For example, honokiol, obtained from several species of Magnolia, was found to inhibit the production of molecules associated with tumour progression and drug resistance in many types of cancers. In NB, it induces autophagic apoptosis through a tumour protein P53 (p53)-dependent pathway [14,15]. Another interesting example is that of products derived from garlic (Allium sativum), which include alliin that originates from cutting, crushing, or grounding garlic and reacts with the enzyme alliinase to form allicin. In NB cell lines, allicin reduced cell division and viability [16]. Moreover, foods from the MD present an interesting option for sources of natural compounds. For instance, in NB cells, an antioxidant that is present in red wine named resveratrol induced cell cycle arrest and apoptosis, and these effects were translated to mice, where the compound presented anticancer effects [17]. Another interesting example is that of lycopene, which is a pigment that is generally present in tomatoes and red fruits and has antioxidant properties, which are fundamental in protecting NB cells against oxidative damage and ER stress-induced damage [18]. In fact, the integration of these natural substances with established chemotherapy protocols offers a promising approach to enhance treatment efficacy and mitigate side effects, which are particularly relevant in paediatric cancer treatment [19].

In 2010, UNESCO recognised the Mediterranean Diet (MD) as an intangible cultural heritage of humanity [20]. The term MD was first introduced in 1960 by Ancel Keys, who considered it a diet with low levels of saturated lipids and the ability to diminish cholesterol levels in the blood, although the concept itself is thought to date back several millennia [21,22]. Years later, in 1995, Willet et al. described the MD as being a dietary regimen typical of certain regions of Italy and Greece with notably high life expectancy and low rates of diet-associated diseases [23]. Since the Mediterranean encompasses numerous regions, the cultures of different countries are seen in this diet, as well as a wide variety of ingredients with abundant antioxidants and anti-inflammatory nutrients. Fundamentally, the MD consists of an elevated consumption of vegetables, fruits, legumes, unrefined cereals, and nuts. The total fat intake must be lower than 30%, and the saturated fat intake must be even lower, not reaching 10%. The consumption of alcohol should be moderate, as should the intake of animal protein. Regarding energy content, recent descriptions account for around 2000 kcal/day, with 37% of the total calories accounted for corresponding to fat [21,22]. There are several factors that may have influenced the food elements present in this diet, which elucidate why it has been challenging to precisely define this dietary regimen [21]. General descriptions of the MD usually lack specific details such as proportions. However, certain habits, such as adding olive oil to vegetables and legumes to make them more pleasurable or eating fruit as dessert, were stated earlier by some authors. The description of the number of servings allowed for the design of a diet pyramid with different versions [24]. In 2011, the MD Foundation presented a new revised pyramid presentation, with the purpose of sharing a representation of the MD pyramid within the Mediterranean Region [20].

Olive oil is the main source of fat in the MD. In Ancient Greece, the olive tree was an essential symbol, and this component was used in medicine and religion, as well as in nutrition [23]. The composition of olive oil varies based on factors such as the origin of the olive tree or climatic conditions. In general, approximately 75% of its content consists of oleic acid (C18:1, n-9), a monounsaturated fatty acid (MUFA). It exhibits low percentages of saturated and polyunsaturated fatty acids [25]. In fact, the positive health effects associated with olive oil are linked to the consumption of extra virgin olive oil (EVOO), which contains high levels of the MUFA and 1–2% highly bioactive compounds. Regarding the MUFA, the existence of a single double bond allows for a higher resistance to oxidation and provides antioxidant properties. Bioactive compounds can be categorised into two groups based on their extraction process. The first consists of unsaponifiable compounds, such as squalene, sitosterols, and pigments, and corresponds to the fraction extracted with solvents after saponification of the oil. The second group consists of hydrophilic compounds, including tocopherol and phenolic compounds [26]. Tocopherol presents high vitamin E activity. Vitamin E is an antioxidant vitamin, with described preventive effects for cancer and cardiovascular diseases. Phenolic compounds, such as oleuropein (OLE), hydroxytyrosol (HT), and tyrosol (Tyr), may act as antioxidants in the human body because they possess a hydroxyl group with that function. These compounds are synthesised from tyrosine or phenylalanine and give a bitter and pungent taste to olive oil since they have a complex interaction with the taste buds [21,25,27]. Figure 1 presents examples of polyphenols that can be found in EVOO, as well as their chemical structure [28].

Targeting aging processes, such as the reduction of telomers, changes in epigenetic patterns, cell senescence, and genomic instability, is one of the numerous abilities of olive oil in preventing disease [29]. These hallmarks of aging are often caused by reactive oxygen species (ROS), which, at elevated concentrations, cause damage to biomolecules such as DNA or proteins. The main production site of ROS is the mitochondria through the reduction of O₂ to H₂O during oxidative phosphorylation. As previously mentioned, the phenolic compounds in olive oil have antioxidant properties, allowing for the repression of damage caused by free radicals [21]. Moreover, olive oil has been associated with an increase in longevity and therapeutic health benefits for a variety of diseases. For example, in cardiovascular diseases, it lowers the plasma levels of the low-density lipoprotein (LDL) and increases the levels of the high-density lipoprotein (HLD), diminishing the risk of problems. This fundamental ingredient of the MD reduces the risk of cancer as well as inflammatory and autoimmune diseases [30]. The consumption of EVOO has been studied for its potential in the prevention or treatment of cancer. For instance, HT has demonstrated potent antiproliferative effects against human colon adenocarcinoma cells, suggesting a potential role in cancer treatment and prevention [31]. Moreover, the MD has been linked to a reduced incidence of breast cancer, highlighting its preventive potential [32]. Studies have also shown that EVOO phenols can suppress the migration and invasion of bladder cancer cells, providing insight into the potential of EVOO in cancer management [33]. Olive oil compounds have been found to inhibit vascular endothelial growth factor receptor-2 phosphorylation, which plays a crucial role in tumour angiogenesis [34]. Furthermore, phenols from EVOO have been shown to block cell cycle progression and influence the toxicity of chemotherapeutic drugs in bladder cancer cells [35]. The nutrigenomic approach suggests that different EVOO cultivars, owing to their varied phenolic content, could impact cancer prevention and treatment differently [36]. In summary, scientific evidence supports the potential of EVOO, particularly its phenolic compounds, in preventing and treating certain types of cancer. However, it is important to note that most of these studies focused on adult cancers and in vitro or in vivo models, so further research on paediatric cancers is needed.