Olive Oil Effects on Colorectal Cancer
Colorectal cancer (CRC) is the third most common cancer per incidence worldwide, the third inmen and the second in women (746,000 and 614,000 cases, 10.0% and 9.2% of the total respectively).More than half of the cases of CRC occur in industrialized regions of the world [1]. CRC patientsshow a 5-year survival of 64% in the United States, with a similar number of deaths in the two sex [2].Following a healthy diet could be a measure of primary prevention for CRC as dietary habits areestimated to contribute to about 50% of CRC cases [3,4]. There is growing evidence that the adoptionof the Mediterranean diet (MD) could represent a protective factor against the onset of various typesof cancer, including CRC [5]. The anti-tumor effects of the MD are largely due to the combination ofantioxidant elements, fiber and polyunsaturated fats [6,7]. A number of studies showed the beneficialeffects of MD, mainly regarding the lower rate of cardiovascular diseases, atherosclerosis, and sometypes of tumors (i.e., intestinal, breast, and prostate cancers) [8]. A meta-analysis of eight studiesshowed a significant inverse association between adherence to MD and incidence of CRC, with a 17%risk reduction for CRC when comparing the highest versus lowest MD categories [9].Olive oil (OO) (Olea europaea, Oleaceae) is a fundamental component of the MD; it is a mix of fattyacids such as oleic and linoleic acid, secoiridoids (oleuropein and oleocanthal), simple phenols (tyrosoland hydroxytyrosol), lignans (pinoresinol), flavonoids (apigenin), hydrocarbons (squalene), triterpenes(maslinic acid), and phytosterols (β-sitosterol). The chemical composition of OO depends on theextraction method used to obtain oil from the olives. Olives are crushed and then the oil is separatedfrom the fruit pulp applying high pressure. Additional processes include extrusion, post-pression orre-pression, with or without the use of hot water. The OO obtained through additional methods showsa stronger colour, weaker flavour, and a higher concentration of free fatty acids [10,11]. Virgin oliveoils (VOOs) are extracted from the olives exclusively by mechanical or other physical means underconditions that does not alter the oil. Extra-VOOs (EVOOs) are obtained from once cold-pressedunfermented olives, and contain a low percentage of free fatty acids (<1%) and the highest phenolslevels
Anti-Inflammatory, Immunomodulatory and Other Anticancer Properties of Olive Oil
Inflammatory response could be modulated by OO polyphenols, which are able to inhibit NF-κBas demonstrated in bothin vitroandin vivostudies. The inhibition of NF-κB results in low expressionof IL-6, IL-8, IL-1βand COX-2, with a consequent creation of a microenvironment that hinders cancergrowth [73,74]. Beauchamp et al. observed that decarboxy methyl ligstroside aglycone (also known asoleocanthal) possesses an anti-inflammatory action similar to that of ibuprofen. In fact, both moleculesare able to inhibit cyclooxygenase (COX) enzymes involved in the biosynthesis of prostaglandins [75].The anticarcinogenic and antithrombotic effects of COX inhibitors, such as ibuprofen and aspirin,are well known [76,77]. It is possible that the administration of oleocanthal may help to reduce thedevelopment of inflammatory bowel diseases (IBD) (ulcerative colitis and Crohn’s disease), and inturn to decrease the risk of CRC [78,79]. IBD represent a major risk factor for the development oCRC [80,81]. Although CRC occurs in a small number of patients with IBD (1%), it shows a highmortality and is responsible for 20% of IBD-related mortality [82].A study conductedin vivoon rats with azoxymethane induced CRC suggested thechemopreventive effect of OO against colon carcinogenesis. The antitumor activity seems to berelated to the modulation in colonic mucosa of arachidonic acid metabolism and prostaglandinE2 synthesis, exerted by n9 and n3 fatty acids (oleic acid and eicosapentaenoic acid respectively)present in OO [35]. The phenolic compounds in OO, besides to anti-inflammatory properties,showed also immunomodulatory effects. The immunomodulatory properties could reduce chronicinflammation in IBD and also in other immune-mediated pathologies, such as multiple sclerosis,psoriasis, rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel diseases [83].The primarily involved cells in the autoimmune and inflammatory responses are T lymphocytes andantigen presenting cells (APCs), which are B cells monocyte/macrophages and dendritic cells [84].Raised levels of inflammatory cytokines (i.e., TNF-alpha, IL-8, IL-10, IL-6, IL-17) and activation ofinnate adaptive immune cells are involved in the pathogenesis and evolution of IBD. On this basis,cytokine pathways modulating drugs could be used in IBD, although side effects and symptomsrecurrence are common [85]. Dietary OO phenols seem to change clinico-pathological history in IBD,due to their anti-inflammatory properties [86].Apigenin belongs to the subclass of flavonoids in OO and has been widely used in traditionalChinese medicine for centuries. Apigenin has been demonstrated to show anti-tumor propertiesin colorectal, liver, breast, lung, and prostate cancer, with low toxicity and no mutagenicactivity [87]. Apigenin showed dose-dependent activity on proliferation, migration and invasionin CRC, modulating signaling pathways such as JAK/STAT, PI3K/AKT, NF-κB, MAPK/ERK,and Wnt/β-catenin pathways [36,87]. It has been observed that apigenin had a synergistic action withABT-263, a BH-3 mimetic, on CRC cells apoptosis by blocking functions of Bcl-2 family proteins [37,88].Based on these findings, apigenin could be used as dietary supplement or in combination withchemotherapeutic drugs for CRC treatment [89].Luteolin is another natural flavonoid contained in glycosylated form in OO. Glycosylated luteolinis hydrolyzed to free luteolin during intestinal absorption. With other phenolic antioxidants, luteolindemonstrated different beneficial properties on inflammation, oxidation, and cancers [90]. Luteolinmodulated the G2/M cell cycle arrest and caused apoptosis in CRC cells [38]. Also, luteolin blockedthe cell diversion to CRC by epigenetically activating the nuclear factor erythroid 2-related factor2 (Nrf2)/antioxidant-responsive element (ARE) pathway [39].Maslinic acid (MA) is a triterpene found at high levels in the waxy skin of olives. A study bySànchez-Quesada et al. demonstrated that MA modulated the inflammation process by stimulating theproduction of, IL-1α, IL-1βand IL-8, increased IFN-γlevel, which led to M1 polarization, and did notaffect the levels of NF-κB or nitric oxide (NO). These findings suggested that MA could prevent chronicinflammatory response, which is involved in carcinogenesis [91]. MA was also demonstrated to induceapoptosis via the intrinsic apoptotic pathway associated with mitochondria in HT29 colon cancercells [41]. Another study showed that MA may induce apoptotic cell death via the extrinsic apoptoticpathway in Caco-2 colon cancer cells, leading to the cleavage of caspases -8 and -3, and to an increaseof t-Bid levels, in a dose-dependent way [40]. Given the possibility to activate both apoptotic pathways,MA could represent a natural compound with chemotherapeutic or chemopreventive actions in CRC.β-sitosterol, a phytosterol found in OO, inhibited significantly the growth of COLO 320 DM cells,in a dose-dependent way, caused apoptosis by scavenging ROS, and suppressed the expressionof beta-catenin and proliferating cell nuclear antigen (PCNA) in human colon cancer cells [42].A case-control study carried out in a Chinese population, showed that the consumption of phytosterols,includingβ-sitosterol, campesterol and campestanol was associated with a reduction of CRC riskmaking it a potential anticancer drug for colon carcinogenesis
Effects of Olive Oil on Gut Microbiota
The gut microbiota is represented by a composite and dynamic population of microorganismsfound in the human gastrointestinal tract, which strongly influence the host as regards homeostasisand diseases [100]. Some studies showed the fundamental impact of diet in shaping the gut microbiotaacross the lifetime [101]. There is growing evidence that the gut microbiota may play a crucial rolein the development and evolution of gastrointestinal malignancy [102–104]. The interaction betweenmucosal inflammation, oxidative stress and gut microbiota may influence the pathogenesis of CRCin patients with IBD [105]. OO consumption is proven to influence the composition of intestinalmicrobiota; some studies highlighted a significant modulation effect of dietary polyphenols on thecolonic microbial composition or activity, with a possible role on cancer prevention [106,107]. The intakeof OO polyphenols may favour a healthy gut microbiota, increasing bifidobacteria and the amount ofintestinal IgA-coated bacteria [83]. However, the mechanisms underlying the association between gutmicrobiota and carcinogenesis are not fully established.A study by Miene et al.analyzed the effects of 3,4-dihydroxyphenylacetic acid and3-(3,4-dihydroxyphenyl)-propionic acid, which are metabolites of quercetin and chlorogenic acid/caffeicacid, respectively, in human colon adenoma cells LT97. The results showed an enhancement ofglutathione S-transferase T2 (GSTT2) expression and a decrease of COX-2 that could explain thechemopreventive action of polyphenol metabolites after intestinal degradation [43]. A study byKang et al. observed that caffeic acid may inhibit colon cancer metastasis and neoplastic celltransformation by suppressing mitogen-activated MEK1 and TOPK activities [108]. Polyphenols andflavons found in OO (i.e., epigallocatechin-3-gallate, and quercetin) could have anticancer propertiesmediated by gut biotransformation [109–111].Stoneham et al. hypothesized that OO may affect secondary bile acid patterns in the boweland, in turn, modulate polyamine metabolism in colonic cells decreasing the progression sequencefrom normal mucosa to adenoma and carcinoma [112]. Bile acids promote the growth and activityof 7α-dehydroxylating bacteria, which convert primary into secondary bile acids with tumorigenicproperties, principally deoxycholic acid (DCA). Bile acids are able to modify the intestinal microbiotacomposition due to their antimicrobial activity. Based on these observations, dietary intervention,including intake of OO, could reduce CRC risk through its effects on colonic microbial metabolism [113].Ellagic acid is another polyphenol found in OO, that showed a number of biological propertiessuch as antioxidant and cancer protective effects on different tumour cell lines, for example Caco-2colon, Hs 578T breast, MCF-7 breast, and DU 145 human prostatic cancer cells, without any toxicity onnormal human lung fibroblasts
OO contains a variety of beneficial substances that could be helpful for the prevention or thepossible treatment of CRC. The large body of evidence supports the chemotherapeutic potential ofsubstances found in OO against CRC, acting on different sides, such as inflammation, oxidativedamage, and even epigenetic modulation. It is noteworthy that waste products from OO extractioncould be used to produce food supplements with potential effects on cancer prevention. There arefew studies reviewing the association between intestinal microbial composition and function andCRC occurrence. However, the strict interaction between OO polyphenols and human microbiotaseems to have a beneficial effect on CRC. In conclusion, the consumption of OO should be suggestedin a healthy diet instead of other types of oils. The main limitations of existing scientific literaturecome from the difficult evaluation of a single nutrient in a complex diet, such as the MD. Moreover,several studies have been conducted on animals and properties of OO have been assessed principallybyin vitromodels. Further studies and clinical trials are needed to better investigate the beneficialeffects of OO and its components in humans.
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