Template for Electronic Submission to ACS Journals [303083]

[anonimizat]-cancer profile

Annalisa Maruca,a,b‡ Raffaella Catalano,a,b‡ Donatella Bagetta,a,b‡ Francesco Mesiti,a,b Francesca Alessandra Ambrosio,a Isabella Romeo,b,d Federica Moraca,b,c Roberta Rocca,b,e* Francesco Ortuso,a,b Anna Artese,a,b Giosuè Costa,a,b Stefano Alcaro, a,b Antonio Lupiaa,b

[anonimizat]à "Magna Græcia", [anonimizat], 88100, Catanzaro, Italy.

bNet4[anonimizat]à "Magna Græcia", [anonimizat], 88100, Catanzaro, Italy.

[anonimizat] "Federico II", via D. Montesano, 49, 80131, Naples, Italy.

[anonimizat], via Pietro Bucci, 87036 [anonimizat], Italy.

eDepartment of Experimental and Clinical Medicine "Magna Græcia" University, [anonimizat], 88100, Catanzaro, Italy.

‡These authors contributed equally.

*Corresponding author. E-mail address: [anonimizat]

ABSTRACT: [anonimizat]. [anonimizat]-cancer properties owned by several natural products typically from the Mediterranean area. In some regions of the South of Italy, a lower cancer incidence has been observed. There is increasing evidence that adherence to a Mediterranean dietary pattern correlates with reduced risk of several cancer types. [anonimizat]. [anonimizat], [anonimizat]-target profiles.

Keywords: Natural products; Multi-target; Anticancer; Mediterranean products; Mediterranean diet; Anti-oxidant; Anti-proliferative.

INTRODUCTION

1.1 [anonimizat], natural products have been always used in the treatment of cancer1. Actually, it has been estimated that about 70% [anonimizat], widely adopted in clinical use2, have been extracted from natural products3. Classical examples are those of vinca alkaloids4, etoposide, teniposide5, irinotecan and taxanes6. Such drugs are highly effective against a wide range of cancers; nevertheless, they suffer of some limitations such as side effects (e.g [anonimizat], cardiovascular and hematologic toxicity) and high costs. Another limitation is that cancer cells resist to these drugs as they go through mutations. Thus, [anonimizat]. Indeed, carcinogenesis is a complex phenomenon that involves many signaling cascades. Therefore, [anonimizat]: [anonimizat], due to their multiple actions on several targets with different mechanisms of action. [anonimizat], flavonoids, lignans, saponins, [anonimizat], enzymes and signaling pathways7. [anonimizat]i-cancer activity by activating proapoptotic members Bax and Bak, activating p53 and causing a down-regulation of signaling transduction of antiapoptotic protein Bcl-2. They can also act on the cell cycle, inducing cell cycle arrest in G0/G1, G2/M, and S phases. Flavonoids (including all the six subclasses: flavonols, flavonones, anthocyanins, flavones, isoflavones, and flavan-3-ols) act to inhibit processes involved in carcinogenesis such as proliferation, inflammation, invasion, metastasis, and activation of apoptosis. For instance, flavonoids like quercetin, kaempferol, luteolin, epicatechin, catechin, cyanidin exert their anti-cancer activity on several cancer cell lines with different mechanisms of actions: decreasing phosphorylation of epidermal growth factor receptor; increasing DNA fragmentation; counteracting angiogenesis in cancer cells; inhibiting enzymes such as xanthine oxidase, COX-2, lipo-oxygenases, and ornithine decarboxylase; inhibiting signal transduction enzymes such protein kinase C, PI3K, AKT8, 9.

Alkaloids, especially steroid alkaloids, are also used in the treatment of cancer since they can act inhibiting the proliferation of cancer cells with different mechanisms as described by Jiang et al.10 and Lu et al.11:

Inducing apoptosis by activating cell cycle arrest at G1 or G2/M phases;

Inhibiting various enzymes, such as N-acetyltransferase, COX-2 and telomerase;

Regulating various cyclin-dependent kinase proteins and Bcl-2 proteins;

Inducing the production of reactive oxygen species (ROS) in cancer cells;

Inhibiting various regulatory factors of metastasis and angiogenesis, such as NF-ĸb focal adhesion kinase and VEGF;

Inhibiting topoisomerase I enzyme;

Up-regulating tumor necrosis factor receptors (TNFRs).

Other plant-derived molecules are instead used as chemopreventive compounds aimed reducing the morbidity and mortality of cancer, such as resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, is currently in phase I studies in colorectal cancer patients (ClinicalTrials.gov Identifier: NCT00256334). Bioactive plant-derived compounds are characterized by a variety of different mechanisms of action, based on the alteration of several signal transduction pathways involving multiple transcription factors like NF-ĸB, AP112 and Nrf2. This latter is the main target of chemopreventive compounds13.

Anti-cancer properties have been also discovered in psoralen, a natural compound belonging to the chemical class of furocoumarins, which is present in the essential oil of Bergamot14, 15. Capsaicin is also a natural phytochemical isolated from red pepper and exerts strong anti-cancer and chemopreventive functions in pancreatic, prostatic, liver, skin, leukemia, lung, bladder, colon, and endothelial cells16, 17 regulating different molecular targets involved in breast cancer, like caspase-3, ROS, Rac1, and HER-218.

This review describes the main natural compounds native of the Mediterranean areas highlighting their multi-target anti-cancer mechanisms of action (Figure 1).

Figure 1. The polypharmacology effects of natural compounds and functional foods in the main cancer pathways.

1.2 Polypharmacology in cancer therapy

Currently, the standard treatment for cancer involves the use of drug cocktails, containing several inhibitors that target the specific single target. The administration of compounds with multi-target activity towards different oncotargets represents an efficient, logical and alternative approach to drug combinations. A growing interest in this approach is also shown by a steady increase in the number of multi-protein targeting articles published in the last years. Indeed, multi-targeting agents can show either additive or synergistic effects and can also offer advantages for the solution of limited efficiencies, poor security and resistant profiles of a single target. Usually, drug cocktails have complex pharmacokinetics problems and the possibility to establish drug-drug interactions. On the contrary, the administration of a single compound with a multi-target profile allows the simultaneous presence of the molecule at different sites of action of its multiple targets. Finally, preclinical and clinical studies of a multi-target drug is a simpler approach than the development of new combination therapies19. Examples of multi-target drug, approved by Food and Drug Administration (FDA) are lenvima (lenvatinib) and cabozantinib, marketed under the trade name cabometyx. Lenvima inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors, that is VEGFR1, VEGFR2 and VEGFR320, while cabozantinib is a dual-targeting inhibitor of the tyrosine kinases c-Met and VEGFR2; and has been shown to reduce tumor growth, metastasis, and angiogenesis21.

1.3 Importance of Mediterranean area products in cancer

Mediterranean diet (MD) has generally been associated with a decreased risk of developing different diseases, including cardiovascular and neurodegenerative pathologies. Several studies have also demonstrated the relationship between cancer and MD, since it has been estimated that only 5-10% of cancer cases are linked to genetic causes, while 90-95% can be attributed to the environment and bad lifestyle22. In particular, cancer risk increases from 1.2 to 1.5 in overweight individuals and from 1.5 to 1.8 in obese people23. This incidence of cancer is decreased in the population of the Mediterranean Sea and it is attributed to their healthier dietary habits24, 25. Scientific evidences have shown that the adoption of the Mediterranean diet is a protective factor against the onset of various types of cancer, such as esophageal and gastric cancer26, prostate27, breast28, colorectal29, pharynx and larynx cancer30, pancreatic cancer31. The protective role of Mediterranean diet towards neoplastic diseases is mostly due to the high consumption and balanced combination of fruit and vegetables, fish, cereals, fiber, olive oil rich in both monounsaturated and polyunsaturated fatty acids (omega-3 and omega-6) and in polyphenolic compounds such as tyrosol, hydroxytyrosol, and oleuropein and anti-oxidant elements23. Thus, the role of main components of the MD in the prevention of several cancers type has been recently described in several scientific manuscripts. In this review, our aim is to report the main studies that have been held to investigate the role of the main bioactive components of the Mediterranean area products in cancer prevention and their protective action on cancer risk, with a particular focus on their multi-target profile.

MEDITERRANEAN PRODUCTS WITH MULTI-TARGETING ANTICANCER COMPONENTS.

2.1 Extra-Virgin Olive Oil (EVOO)

Several evidences have shown that the adherence to MD leads to a low incidence of cancer thanks to the intake of high phenols food such as olive products32. Generally, the main components in olive oil can be divided into saponifiable and unsaponifiable fractions. The former represents around the 98% of total weight and consists in glycerides, saturated and unsaturated fatty acids (stearic acid, palmitic acid, linoleic acid, meristic acid and oleic acid), while the latter represents at least the 1% of total weight.33 The unsaponifiable fraction is composed by at least more than 200 components not chemically-related to fatty acids34. Hydrocarbons, sterols, triterpenes, tocopherols, pigments, phenols, and others belong to the unsaponifiable class. Further, phenol compounds can be classified as phenolic acids, phenolic alcohols, flavonoids, and secoiridoids. The latter are exclusively present in Oleace family, whereas other derivatives are also widely present in other botanical groups35. Among all, phenolic compounds have been extensively studied considering their anti-oxidative profile and the health beneficial associated36. The content of phenols derivatives in olive oil change in according with several factors, but it is strongly influenced by its production and storage37. Surely, the amount of phenols is higher in extra-virgin olive oil (EVOO) than the refined oil38. Tyrosol (TY) and hydroxytyrosol (HT) are the major phenols alcohols in olive oil and oleuropein (OL) is the main secoiridoid in olive fruits (Table 1). HT is produced by enzymatic cleavage of OL, and its amount is strictly correlated with the oxidative stability of olive oil.

Table 1. Most representative compounds in EVOO.

The anti-cancer activity of OL and HT is primarily related to their anti-oxidant activity, including the protection against the genotoxic action of ROS41 and the influence on genes expression involved in the development of neoplasia42, 43. In previous studies, olive phenols have shown anti-cancer activity in several cancer cell lines such as pancreatic44, breast45, prostate46, and colorectal47. Furthermore, it has been demonstrated that HT and OL are able to discriminate between normal and cancer cells and to induce apoptosis only in the latter cell lines46. In particular, considering the chemical structure similarity of OL and HT with estradiol (both present aromatic ring), it has been hypothesized the possibility that these phenols compete with estrogen receptor (ER) binding site48. Indeed, over-exposure to estrogen could be considered as factor risk to develop breast cancer49, which growth is positively influenced by estradiol, ER agonist. Consequentially, ER has been received a lot of attention as target for breast cancer treatment or prevention. HT and OL prevent cell proliferation in MCF-7 breast cancer cell line by inhibition of estrogen activated ERK1/2 signaling pathway50. Moreover, OL is able to inhibit cell proliferation in MCF-7 at the S-phase of the cell cycle through up-regulation of p21 gene and inhibition of NF-KB45. Furthermore, Chimento et al. 51 demonstrated that OL and HT can be considered as inverse agonists of GPER receptors leading to apoptosis of ER-negative SKBR3 breast cancer cells. GPER is a G-protein coupled estrogen receptor and when activated lead to an increasing of ERα-negative breast cancer proliferation. By docking studies, it was highlighted that both OL and HT displayed a good affinity for GPER. Deeply, OL established several hydrogen bonds with the residues Tyr142, Gln216, Glu275, Asn276, and His307. Further, the complex ligand-protein was better stabilized by a series of hydrophobic contacts. In the case of HT, hydrogen bonds were observed with the residues Ser134 and Glu275. Furthermore, the aromatic ring of HT established π- π stacking with Phe208. Finally, interesting evidence comes from the study carried out by Coccia et al., about the capacity of EVOO phenols to suppress the migration and invasion of T24 Human Bladder Cancer Cells (T24-HBCC)48. Even if the cell adhesion has not been compromised by EVOO extract, phenolic components have caused a tremendous decrease of T24-HBCC migration and invading cell capability in a dose-dependent manner. Moreover, considering that MMP-2 and MMP-9 have been associated with the proteolytic degradation of the extracellular matrix that occurs during tumor invasion52, the capability of EVOO extracts to inhibit these enzymes have been evaluated. It has emerged that extra-virgin olive oil extract, not only has reduced the activity of MMP-2, but also has down-regulated the expression of MMP-2 gene in T24 cell53.

2.2 Tomato

Tomato is a member of an important plant family called Solanaceae, and its derived products have a very interesting nutritional value joined to important anti-oxidant, anti-inflammatory, and anti-cancer activities. From a nutritional point of view, tomatoes contain interesting amounts of moisture (95%), carbohydrates (3%), protein (1.2%), total lipids (1%), minerals, and vitamins (vitamins A and C, thiamin, riboflavin, niacin, pantothenic acid, and pyridoxine)54-58. Moreover, they represent a good source of phenolic compounds (phenolic acids and flavonoids), carotenoids (lycopene, β-carotene) and glycoalkaloids (tomatine). In particular, isoprenoids constitute a very representative group of chemical constituents present in tomato and they include lycopene, β-carotene, γ-carotene, ζ-carotene, phytoene, phytofluene, lutein, neoxanthin, violaxanthin, α-cryptoxanthin, zeaxanthin, β-cryptoxanthin, cyclolycopene, neurosporene, and β-carotene-5,6-epoxide (Figure 2).

Figure 2. Chemical structures of the main carotenoids present in tomato.

The most studied tomato constituent with confirmed anti-oxidant and anti-cancer activities is the lycopene. It has a long-chain structure with a higher number of conjugated double bonds that are responsible for its anti-oxidant activity, 10 times higher than vitamin E59, 60. Lycopene is recognized as the most beneficial tomato compound with distinct health-promoting effects, particularly recent findings have suggested the lycopene tuning ability in intercellular communications in metabolic and immune system pathways61. However, rather than through free radical scavenging, a target of lycopene could be the Keap1-Cul3-Rbx ligase complex, which ubiquitinates IKK and prepares it for degradation by the proteasome. Under oxidative stress, or possibly through Keap1 mutations in certain cancers, Keap1 is modified and releases IKK, thus allowing it to phosphorylate IκB and activate the NF-B pathway62. One further mechanism of action of this compound is the inhibition of leptin-mediated cell invasion and MMP-7 production in HT-29 cells. In particular, lycopene could enhance the expression and stability of E-cadherin proteins. Since MAPK/ERK and PI3K/Akt signaling pathways play important roles in leptin-mediated MMP-7 expression and cell invasion, lycopene could effectively inhibit the phosphorylation of Akt, glycogen synthase kinase-3β (GSK-3β) and ERK 1/2 proteins. Finally, the molecular mechanism of lycopene is expressed in part through the decrease in nuclear levels of AP-1 and β-catenin proteins63.

2.3 Wine

Moderate wine (mostly red) drinking is part of the MD, together with abundant and variable plant foods, high consumption of cereals, olive oil as the main (added) fat and a low intake of (red) meat. This healthy diet pattern concerns a “Mediterranean way of drinking”, that is a regular, moderate wine consumption mainly with food (up to two glasses a day for men and one glass for women)64. Wine is a traditional alcoholic beverage obtained by fermentation of grape must, which quality is related to the composition and variety of grape. Wines can be differentiated by the geographic location of vineyards, variations in the same vineyard, different viticulture practices, and aging techniques. It is a complex mixture of several hundred compounds, however, in general, the average concentrations of the major components of wine are water, 86%; ethanol, 12%; glycerol and polysaccharides or other trace elements, 1%; different types of acids, 0.5%; and volatile compounds, 0.5%. Red wine, obtained by the alcoholic fermentation of must in the presence of skins and seeds is known to contain 10-fold more phenolic compounds than white wine, exclusively produced by the fermentation of grape juice65. In particular, among the bioactive components of wine, resveratrol (Figure 3), acting on diverse mechanisms simultaneously, it has been emphasized as the most promising, multi-target anti-cancer agent in red wine, relevant in both cancer prevention and treatment.

Figure 3. 2D structure of resveratrol.

Resveratrol (trans-3,4′,5-trihydroxystilbene) is a non-flavonoid polyphenol belonging to the stilbenes, secondary metabolites produced by plants in response to stressful conditions, such as fungal infections and UV radiations. Resveratrol, naturally occurring in some plant foods, but especially contained in grapes and red wine, is the most investigated and well-known member of this class of compounds. Interest in resveratrol first arose after it was hypothesized to be the most responsible agent of the apparent health benefits of red wine. Since then, the research has shown resveratrol to have different pharmacological effects, such as potential anti-cancer, anti-inflammatory, cardioprotective, and neuroprotective activity66. Several studies have evidenced that resveratrol provides a broad range of preventive and therapeutic alternatives against various diseases including different types of cancer. Indeed, its anti-cancer effect has been investigated in depth, and several research papers and reviews have been published in the past years since Jang et al. first reported its in vivo antitumor properties in 199767. Such data demonstrated that resveratrol explicates anti-cancer activity interacting with many molecular and biochemical targets68 involved in the different phases of carcinogenesis, including initiation, promotion, progression, invasion and metastasis. A further contribution comes from the anti-oxidant, anti-inflammatory and immunomodulatory properties which decreasing injury induced by oxidative stress (DNA damage, protein oxidation, and lipid peroxidation) and enhancing immune onco surveillance. Therefore, many chemopreventive and chemotherapeutic mechanisms to prevent, arrest, or delay tumor development by resveratrol have been proposed. In general, some of the molecular targets and signalling pathways involved in the anti-cancer effect of resveratrol comprehend: extracellular growth factors; receptor tyrosine kinase; apoptotic pathways; inflammatory pathway; hormone signaling; cell metabolism (red-ox); integrin signaling69. Different studies demonstrated that resveratrol is able to block different carcinogenetic stages mediated by over-expression of growth factors and receptor tyrosine kinases. Acting particularly on EGF, resveratrol suppresses initiation, promotion, and progression of carcinogenesis, while reducing VEGF expression and promoting NOS activity it can avoid the formation of more aggressive tumor phenotypes, decrease neo-angiogenesis and the risk of metastasis. In particular, Hogg et al. have investigated and compared the antigrowth effects of resveratrol on 3D cell aggregates of the EGFR/Her-2 positive and negative ovarian cancer cell lines SKOV-3 and OVCAR-8, respectively. Results have shown that resveratrol reduced cell growth in the SKOV-3 and OVCAR-8 in a dose-dependent manner. The growth reduction was mediated by the induction of apoptosis via the cleavage of poly(ADP-ribose) polymerase (PARP-1). In the OVCAR-8 cell line, resveratrol at 5 and 10 µM has increased the activation of Erk. In SKOV-3 line, at higher concentrations, resveratrol has significantly reduced the phosphorylation of Her-2 and EGFR and has decreased the expression of extracellular-signal-regulated kinases (ERK) and vascular endothelial growth factor (VEGF). Thus this study demonstrates that resveratrol may inhibit growth of 3D cell aggregates of ovarian cancer cell lines via different signalling molecules70. Resveratrol has also a beneficial effect on prostate cancer by multi-target mechanism. In fact, it has been demonstrated that it is able to act both on the phosphatase and tensin homolog (PTEN)/AKT pathway (usually deregulated in such cancer type) and to reduces the phosphorylation of mTOR and FOXO71. Park et al. have proved, both by in vitro and computational studies, that resveratrol directly inhibits mTOR in an ATP-competitive manner. Docking simulations have suggested that the binding in the ATP-binding site of mTOR is characterized by the establishment of different hydrogen bonds with both the backbone amide groups and the side chains of Glu2190 and Asp2195. In addition, hydrophobic interactions with non-polar residues further have stabilized the resveratrol binding mode. They also have demonstrated the interaction with Asp2195 is necessary for mTOR-resveratrol binding and thus inhibition. In fact, resveratrol has suppressed wild-type mTOR, but not the mutant obtained replacing the Asp2195 with an alanine residue72. Resveratrol is also able to modulate red-ox signaling, protecting cells from oxidative damage. Specifically, Sengottuvelan et al. have proved that resveratrol supplementation suppressed/prevented the hyperproliferation of colonocytes, ACF and tumor development in the colon, by modulating the pre-carcinogenic events such as DNA damage and pro-oxidant/anti-oxidant imbalances in the rats. In particular, their study has been aimed to estimate the effect of resveratrol on DNA damage in a short-term study of 16 days and circulatory lipid peroxidation, enzymatic/non-enzymatic anti-oxidants status in a long-term study of 30 weeks in 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis. The results have highlighted that DMH-induced DNA damage and oxidative stress have been effectively counteracted by chronic resveratrol supplementation, both by improving enzymatic (superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and glutathione S-transferase) and non-enzymatic (reduced glutathione, vitamin C, vitamin E and β-carotene) anti-oxidant mechanisms73. Different studies have supported the capability of resveratrol to promote the cell cycle arrest, an irreversible process which could lead to the apoptotic cell death. Yu et al. have demonstrated that resveratrol exhibits an inhibitory effect on the proliferation of oral squamous cell carcinoma (OSCC) through the cell cycle arrest in the G2/M phase, the enhancement of cyclin A2/B1 expression and thus induction of apoptosis74. Moreover, Ahmad et al. have manifested that resveratrol, via modulations in cyclin-dependent kinase (CDK) inhibitor-cyclin-cdk machinery, has induced an arrest in a G1 phase cell cycle followed by apoptosis of human epidermoid carcinoma (A431) cells75. Also inflammation is a critical component of tumor progression with a key role within the tumor microenvironment and several types of cancer are favoured by a certain degree of systemic, low-grade chronic inflammation featured by elevated circulating inflammatory biomarkers, in particular cytokines (e.g., interleukin (IL)-8, IL-6, IL-1, and IL-12), prostaglandin E2 (PGE2), tumor necrosis factor α (TNF-α), and interferon (INF). Signalling molecules of the innate immune system are, indeed, involved in cancer invasion, migration, and metastasis, such as selectins, chemokines, and their receptors. Resveratrol is a promising molecule able to target multiple inflammatories, cancer-related sites, simultaneously, i.e., macrophage migration inhibitory factor, COX-2, NF-κB, and AP-1. In particular, this compound is a strong COX suppressor, and an activator of peroxisome proliferator-activated receptor gamma (PPAR-). In addition to the anti-inflammatory effect, the activation of PPAR- exerts anti-proliferative and anti-tumorigenic effects76. By the way, Calleri and co-workers have demonstrated both by chromatographic and crystallographic results that resveratrol interacts directly with PPAR-. They have solved the X-ray structure of the complex between PPAR- ligand-binding domain (LBD) and resveratrol (PDB ID: 4JAZ) at 2.85 Å resolution (Figure 4). Such model has revealed that resveratrol occupies a region near to the -sheet in a position similar to that of other known PPAR- agonist. Particularly, resveratrol engages hydrogen bond with Ser342 by one of its two hydroxy groups of the resorcinol moiety; van der Waals contacts with the side chain of Phe264, His266 and Arg288; electrostatic interactions with Arg288 and Arg280. Unlike other PPAR- agonist, the phenolic portion of resveratrol has occupied a small pocket close to the LBD entrance engaging one hydrogen bond with Arg280 side chain77.

Figure 4. Binding mode of resveratrol within the LBD of PPAR-γ (PDB ID: 4JAZ). The -sheet region is highlighted as yellow cartoon. Hydrogen bond with Ser342 is depicted with dashed black lines.

Remarkably Ren et al. have clarified that resveratrol suppresses TNF-α-induced signalling in a dose-dependent manner, both via nuclear factor kappa-B (NF-κB) activation and via the transcriptional activity of p65, but without affecting the expression of the former or blocking the nuclear translocation of the latter. Further investigations have revealed that resveratrol blocks the ubiquitination of NEMO and inhibits IκBα kinase-mediated NF-κB activation. Therefore, these results have suggested that resveratrol might represent a novel approach to treating cancer also hitting inflammatory contribution78. Considering the effect of resveratrol on transcriptional factors, besides the above described NF-κB, resveratrol also inhibits transcriptional factors, such as the activator protein (AP)-1, AP-2, and CREB, which control genes involved in regulating urinary plasminogen activator (u-PA) and several MMPs. It has been demonstrated by Yang et al. that resveratrol tested on osteosarcoma cells, has reduced their in vitro migration and invasion through transcriptional and epigenetic regulation of MMP-2; this finding has been confirmed by in vivo experiments, which have evidenced a decreased incidence of lung metastasis79. Resveratrol seems to be able to have also influence on integrin signaling, transmembran, specifically on the epithelial-mesenchymal transition (EMT), which has a key role in tumor invasion and metastasis. Resveratrol has inhibited, in a dose-dependent manner, EMT of pancreatic cancer cells, by suppressing both the PI3K/AKT/NF-κB pathway and the EMT-related gene expression (E-cadherin, N-cadherin, vimentin, MMP-2, and MMP-9), crucial for cancer cell motility and metastasis80. Resveratrol, in particular, has been reported to act also on multiple cellular signaling pathways involved in the processes of cancer cell invasion, metastasis, and tumor reaps, mostly on STAT3 are crucially implicated in the embryonic development, in the biology of cancer stem cells (CSCs) and in the acquisition of EMT81. In addition, resveratrol possesses anti-apoptotic activity through multiple mechanisms. Particularly, Shankar et al. have proved that in prostate cancer resveratrol generates ROS, translocates p53 and Bax to mitochondria, regulates Bcl-2 family members and IAPs, and causes the release of mitochondrial proteins. Furthermore, their study has established a direct role of p53 on the caspase-dependent mitochondrial death pathway and has proposed that p53 interacts at the level of the mitochondria influencing resveratrol sensitivity. Gene therapy approach to deliver Smac/DIABLO can also be undertaken to sensitize TRAIL-resistant LNCaP cells. The capacity of resveratrol to sensitize TRAIL-resistant LNCaP cells has suggested that it could be associated with TRAIL for the prevention and/or treatment of prostate cancer82. Finally, the androgenic effect of such compound could be considered a promising novel anti-cancer approach. In particular, resveratrol and dihydrotestosterone (DHT) signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, meanwhile resveratrol promotes apoptosis. Chin et al. have examined the mechanisms of such opposed effect showing that DHT inhibits resveratrol-induced nuclear complex of p53-COX-2 formation, which is required p53-dependent apoptosis. ChIP studies have suggested that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation, which is crucial for the stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive83.

2.4 Onion

Onions (Allium Cepa) are one of the most important vegetable crops and their bulbs are the main edible part of the plant, with a distinctive strong flavor and pungent odor. Onion has been reported as one of the major sources of dietary flavonoids. Indeed, at least 25 different flavonols have been characterized in onion. Quercetin and its derivatives quercetin 4’-glucoside and quercetin 3,4’-diglucoside have been reported as the main flavonols in all onion cultivar, accounting for about 80-95% of the total flavonols84. Quercetin is one of a group of over 4,000 naturally available plant phenolic compounds whose isolation and biological recognition were first described in 193685 and it’s one of the most popular nutritional anti-oxidants existing in foods such as vegetables, fruits, tea, and wine. Chemically speaking quercetin belongs to the class of flavonoids (from flavus which means yellow, their common color), natural products derived from 2-phenylchromen-4-one86. Quercetin is commonly present as a glycoside and is converted to glucuronide/sulfate conjugates during intestinal absorption and only conjugated metabolites are present in circulating blood. Although metabolic conversion attenuates its biological effects, active aglycone may be produced from the glucuronide conjugates by enhanced b-glucuronidase activity during inflammation. In a recent study, two varieties of onions called “Ramata di Montoro” (coppery onion from Montoro) and “Cipolla Rossa di Tropea”, both cultivated in Southern Italy, have been characterized for the first time highlighting their high content of quercetin87. Several studies have been investigated the anticancer activity of quercetin88-90 evidencing its potential to treat cancer thanks to a multi-target mechanism91-93. Their cancer-preventive effects have been assigned to different mechanisms including their anti-oxidative activity, the inhibition of enzymes that promote carcinogens, the regulation of signal transduction pathways, and interactions with receptors and other proteins93. In particular, it has been demonstrated that quercetin suppresses cell growth, inhibits of metastasis and induces apoptosis (Figure 5).

Figure 5. Cancerogenic pathways regulated by quercetin.

Several in vitro studies have showed that quercetin is able to inhibit the cellular growth of different kind of tumors, such as breast cancer94, thyroid cancer95, liver cancer96, colon cancer97, leukemia98, gastric cancer99 and ovarian cancer100. The main mechanisms underlying the inhibition of cell growth seem to be related with the capability of quercetin to interfere with distinct signaling pathways, such as P13K/Akt, Her-2/neu, Wnt/β-catenin and EGF. In fact, a study carried out by Bruning, it has been confirmed that quercetin inhibits the mammalian target of rapamycin (mTOR), often hyperactivated in cancer, which is a crucial regulator of homeostasis controlling essential pathways leading to cell growth, protein biosynthesis and autophagy. mTOR inhibition can further be expected from its interference with PI3K-dependent Akt stimulation, AMP-dependent protein kinase activation and hamartin upregulation, therefore quercetin has the advantage to function as a dual-specific mTOR/PI3K inhibitor101. In addition, Maurya et al. have reported that quercetin regresses Dalton’s lymphoma growth via suppression of PI3K/AKT signaling. More specifically, they have analyzed the quercetin effect in ascite cells of Dalton’s lymphoma mice in terms of cell viability, glycolytic metabolism as well as expression, and level of PI3K, AKT1, and p53. Results have showed hyperactivation of PI3K signaling, leading to activation of AKT1 and inactivation of p53. Maurya et al., measuring the activity and expression of lactate dehydrogenase (LDH-A), have also demonstrated that quercetin is able to down-regulate the glycolytic metabolism. These findings suggest that quercetin may contribute to lymphoma prevention by down-regulating PI3K–AKT1–p53 pathway as well as by glycolytic metabolism102. In fact, decreased energy production due to insufficient LDH-A activity provides tumor cells susceptibility to death103. Jeong and collaborators have observed that quercetin has reduced the level of Her-2/neu protein in time- and dose-dependent manners inducing its polyubiquitination. In particular, when the proteasome pathway has been arrested by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies have revealed that quercetin has enhanced interaction between Her-2/neu and Hsp90, which is a molecular chaperone involved in stabilization of Her-2/neu. Thus, inhibition of Hsp90 activity by a specific inhibitor has caused dissociation of Hsp90 from Her-2/neu, promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, has played a key role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could denote an alteration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu104. Kim et al. have investigated the biological activities of quercetin against mammary cancer cells focusing their attention on the capability of such flavonol to regulate Wnt/β-catenin signaling pathway, since its abnormal activation is associated with the development of breast cancer. In their experiments, quercetin has showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Moreover, the inhibitory effect of quercetin on the Wnt/β-catenin signaling pathway was confirmed by the reduced stabilization of the β-catenin protein94. Firdous et al. have examined the molecular mechanism underlying the chemopreventive effects of quercetin on prostate cancer in an in vivo model. They have demonstrated that quercetin prevents prostate cancer growth via EGFR signaling and prostate cancer progression by regulating cell adhesion molecules like E-cadherin, N-cadherin and vimentin via snail, slug and twist gene. Interestingly quercetin has been effective in preventing carcinogenesis in both dorsolateral and ventral prostate105. Mu et al. have evaluated the therapeutic effect of quercetin on human hepatoma cell line (HepG2) incubating various groups with different doses of quercetin for 12-, 24-, 48- and 72-h time duration and comparing with control groups. Dose- and time-dependent inhibition in HepG2 proliferation has been discovered with quercetin treatment. At 48 h of incubation, 61.78% of the cells have been blocked at G1 phase with 25 mcM/l quercetin while 89.62% have been arrested at G1 phase with 50 mcM/l quercetin. Moreover, the results have indicated that: quercetin has increased the content of Cdk inhibitor p21 protein, which has correlated with the elevation in p53 levels during 12 h of incubation; quercetin has increased the level of Cdk inhibitor p27 protein during 24 h of incubation. From such findings, it can be established that quercetin blocks cell cycle progression at G1 phase and explicates its growth-inhibitory effect through the increase of p21 and p27 and tumor suppressor p53 in HepG2106. Concerning the inhibition of metastasis, various studies have reported the capacity of such onion flavonol to suppress matrix metalloproteinases (MMP), enzymes responsible for degrading extracellular matrix and thus promotion this pathogenic mechanism. In a study performed by Lin et al., quercetin has significantly suppressed MMP-9 gene expression via blocking the protein kinase C (PKC)d/extracellular signal-regulated kinase (ERK)/AP-1- signaling pathway, and consequently reductions in migration and invasion of human breast carcinoma cells have been first identified107. In addition, Huang et al. have previously explored the possible interactions of quercetin with the secretion of MMPs, finding that quercetin could decrease the secretion MMP-9 and MMP-2 in A431 cells. To test the hypothesis that the secretion of MMPs has been inhibited, cell lysates from EGF or flavonoid treated cells have been assayed for gelatinase activity, revealing that quercetin could retain the intracellular concentration of the MMP-9108. As reported in different studies, quercetin is also able to promote cancer cells apoptosis both by acting on the intrinsic and extrinsic pathways. Chien et al. have demonstrated that quercetin induces apoptosis in MDA-MB-231 cells by DAPI staining, DNA gel electrophoresis and flow cytometric analysis. They have identified two caspase-associated apoptotic pathways which contributed to the cytotoxic effects of quercetin. One pathway is associated with the Fas receptor resulting in caspase-8 activation and activation of caspase-3, which altered the balance of Bax/Bcl-2. This effect then has caused the release of cytochrome c and activation of caspase-3. They also have found that quercetin reduced Bcl-2 protein levels and increased levels of Bax in MDA-MB-231 cells109. Kim et al. have determined the mechanism of quercetin-induced apoptosis in HT-29 colon cancer cells. Remarkably, quercetin has promoted cell cycle arrest in the G1 phase and up-regulated apoptosis-related proteins, such as AMPK, p53, and p21, within 48 h. Furthermore, in vivo experiments have reported that quercetin treatment has resulted in a significant reduction in tumor volume over 6 weeks, All of these outcomes indicate that quercetin induces apoptosis via AMPK activation and p53-dependent apoptotic cell death in HT-29 colon cancer cells and that it may be a potential chemopreventive or therapeutic agent against HT-29 colon cancer110. Finally, in subsequent work, it has been revealed that quercetin induces apoptosis by reducing mitochondrial membrane potential, generating intracellular ROS production and increasing sestrin 2 expression through the AMPK/p38 pathway111.

2.5 Garlic

Garlic is a bulbous cultivated plant, traditionally assigned to the Liliaceae family and it contains many biologically and pharmacologically active compounds, which are beneficial to human health acting against a number of diseases, with particular regard to the cardiovascular system and the prevention of cancer. Fresh garlic contains water, carbohydrates, proteins, fiber, fat, minerals, vitamins and 33 organosulfur compounds (OSCs)112, 113. The main OSCs are allicin, diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS) and ajoene (Figure 6).

Figure 6. Chemical structures of the main sulfur compounds in garlic.

Cancer chemopreventive effects of OSCs are based on several mechanisms, including modulation in activity of several metabolizing enzymes that activate and detoxify carcinogens and inhibit DNA adduct formation, anti-oxidative and free radicals scavenging properties and regulation of cell proliferation, apoptosis and immune responses114. Studies have revealed that OSCs inhibit phase 1 enzymes and increase the expression of phase 2 ones114, 115. Thus, OSCs function in the prevention of chemically induced cancers is related not only to the inhibition of carcinogen activation but also to the increasing detoxification of the activated carcinogenic intermediates through induction of phase 2 enzymes. For example, DAS and its metabolites diallyl sulfoxide and sulfone competitively inhibit the activity of cytochrome P-450 2E1 in a time- and NADPH-dependent manner116. Singh et al. have observed that DADS mediated suppression of H-ras oncogene-transformed tumor growth correlated with a decrease in hepatic and tumoral HMG-Co A reductase activity, leading to the inhibition of membrane association of p21117. Another mechanism is related to the selective inhibition of cell cycle progression in cancer cells, that can be linked to a decrease in complex formation between cyclin-dependent kinase 1 (CDK1) and cyclin B1, leading to the suppression of the kinase activity of CDK1/cyclin B1 complex118 and to c-Jun N-terminal kinase (JNK)-dependent generation of reactive oxygen species (ROS)119. Several studies have also showed that microtubule network can be affected by OSCs in cancer cells, leading to mitotic block or apoptosis. In particular, the S-allylmercapto cysteine causes rapid microtubule depolymerization and cytoskeleton disruption in interphase cells120. Moreover, in response to a variety of OSCs, including allicin, S-allylmercapto cysteine and S-allyl cysteine, increased histone acetylation and correlated growth inhibition has been observed121. Interestingly, recent data have showed that garlic-derived products impart strong cancer chemopreventive as well as cancer therapeutic effects, thanks to their ability to modulate cell-signaling pathways in a fashion that controls the unwanted proliferation of cells73.

2.6 Saffron

Saffron is the dried stigmas of Crocus sativus L., a member of the large family Iridaceae. It has aroused much interest because, in addition to being used as a flavoring agent, pharmacological experiments have established numerous beneficial properties including the radical, anti-mutagenic and immuno-modulating scavenging action122. Moreover, bioactive compounds of Crocus sativus L. resulted active as human monoamine oxidases inhibitors123 and promising anti-Helicobacter pylori, anti-malarial and anti-leishmanial agents123. From a chemical point of view, it contains more than 150 volatile, non-volatile and aroma-yielding compounds, consisting of sugars, minerals, fats, vitamins, secondary metabolites and different pigments, such as lycopene, α- and β-carotene, zeaxanthin, crocetin (liposoluble) and crocins (hydrosoluble). The three main chemical constituents are represented by crocin, crocetin and safranal (Figure 7)124.

Figure 7. Chemical structures of the main saffron constituents.

Many in vitro e in vivo studies have shown significant anti-proliferative effects of crocin on several types of human cancers, such as colorectal, breast, gastric and ovarian cancer, leukemia and lung adenocarcinoma, but surprisingly, it has exhibited no significant effect on the growth of non-cancerous cells. Several molecular mechanisms are reported in literature to explain its anti-proliferative behavior125. Bajbouj et al.126 have proposed the interaction with DNA topoisomerase enzymes as responsible for the inhibitory effect of crocin on cell proliferation. Moreover, Sun et al.127 have investigated the inhibition of synthesis of DNA and RNA as another mechanism of crocin's effect on cancer cells, especially in a human tongue carcinoma cell line (Tca8113); even if its detailed mechanism is still obscure128. Recently, it has also shown that the preference for cancer cells can be associated with the ability of crocin to inhibit microtubule assembly and to induce aggregation of tubulin at higher concentrations. In particular, Naghshineh et al. have evaluated before anti-microtubule activity of safranal by turbidimetric method and transmission electron microscopy (TEM). They showed a significantly decrease of microtubule polymerization in the presence of safranal, while molecular docking was performed to estimate safranal binding with tubulin. Hydrogen bond with Gly142 and hydrophobic interactions played critical roles for the safranal binding a stabilization between α and β tubulin. Tubulin changes its structure after safranal bindings between alpha and beta subunit, leading to the decline of tubulin assembly129. In addition, it has been observed that vinblastine inhibits the crocin binding to tubulin, by suggesting that crocin binds at the vinblastine site on tubulin130. On the other hand, Kim et al. have demonstrated that crocin inhibits the activation of protein tyrosine kinases JAK1, JAK2 and c-Src, leading to the suppression of the constitutive STAT3 activation. This is followed by the down-regulation of the expression of downstream gene products such as anti-apoptotic (Bcl-2), pro-apoptotic (Bax), invasive (CXCR4), angiogenic (VEGF) and cell cycle regulator (cyclin D1) genes, which are correlated with the accumulation of cells in sub-G1 phase of cell cycle and induction of apoptosis131. Different studies have shown crocin as an anti-cancer compound interacting with DNA and causing epigenetic alternations132. Thus, Hoshyar et al. have investigated the interaction of the major saffron carotenoids, such as crocin and crocetin, with oligonucleotides, showing that crocin significantly interacts with DNA, especially G-quadruplex and I-motif conformations. This mechanism, in addition to the anti-oxidant power, is shared with crocetin and safranal133. Finally, Granchi et al. observed that crocetin inhibit lactate dehydrogenase (LDH), whose inhibition represents an innovative approach to fight cancer, since this peculiar glycolytic metabolism is characteristic of most invasive tumor cells.134

2.7 Hazelnut

Hazelnuts produced by Corylus avellena L., which belongs to the genus Corylus, and family Betulaceae’s are widely consumed all over the world, and the common hazel is widely distributed along the coast of southern Europe and the Black Sea region. Italy is the world’s second largest producer of hazelnuts (Corylus avellana L.) after Turkey 135. Hazelnuts are used as an ingredient in the production of a great variety of manufactured food136. Hazelnuts are nutrient nuts with complex matrices rich in unsaturated fatty acids and other bioactive compounds such as high-quality vegetable protein, fiber, minerals, tocopherols, phytosterols, selenium and folic acid. By the advantage of their exclusive composition, hazelnuts are likely to beneficially health impacts and their consume could intervene in the prevention of cancer, in fact epidemiologic studies have associated hazelnut consumption with a reduced incidence of the risk of certain chronic diseases such as cancer137. The nutrients contained in hazelnuts may modify specific processes related to cancer development such as the regulation of cell differentiation and proliferation, the reduction of tumor initiation or promotion, the DNA protection and the regulation of immunological and inflammatory responses. In addition, some hazelnut’s components are related with antioxidant activity, with the repair of DNA damage, with the induction or inhibition of metabolic enzymes and hormonal mechanisms138. The β-sitosterol and the phytosterols contained in the hazelnut have a protective activity against different types of cancer such as breast, colon, colorectal and prostate cancer137. The β-sitosterol is presently under intense study for its capacity to stop tumor growth and to induce programmed cell death in cancer cells139. Also the α- and γ-tocopherol, that are present in highest quantities in hazelnuts, helps to lower the risk of certain types of cancer140. There is an evidence (AIRC & WCRF 1997) confirmed by numerous experimental studies in animals and cultures of cell lines, showing that α-tocopherol can inhibit cell proliferation and therefore can influence the reduction of carcinogenesis. Numerous observational epidemiological studies in humans have shown that high consumption of vitamin E can protect against various tumor locations138. The presence of some phenolic compounds, such as quercetin, which belongs to the flavonoid group, and resveratrol, which belongs to the groups of the stilbenes, has been described as anti-oxidants compounds, in vitro studies, have suggested that these polyphenols may be able to reduce chemically-induced carcinogenesis and they also inhibit the proliferation and the trigger apoptosis of cancerous cells138. Phenolic and polyphenolic compounds constitute an important class of secondary plant metabolites that act as free radical scavengers and as inhibitors of LDL cholesterol oxidation and DNA breakage141. These activities suggest that hazelnuts could potentially be considered as an excellent and readily available source of natural anti-oxidants142. In addition, quercetin and resveratrol act on the formation of the prostaglandins and pro-inflammatory cytokines that intervene in the inflammatory process. This mechanism is important in tumors that have a component of chronic inflammation, such as colorectal cancer, stomach cancer, cancer of the pancreas and cancer of the cervix. However, there is no solid epidemiological evidence to prove these hypotheses. The presence of the folic acids in the hazelnuts have an important role in the anti-cancer activity. It is well known the relevance of the folic acid in the metabolism and the synthesis of DNA, in fact it acts as a coenzyme in the synthesis of nucleic acids and the metabolism of amino acids. Therefore, it is fundamental to the processes of DNA synthesis, methylation and repair. A folate deficiency may favor chromosome rupture and genetic instability. Although the ruptures can be repaired, the chromosomes become fragile and the risk of cancer increases. Scientific evidence from observational epidemiological studies shows that a diet low in folate can increase the risk of colorectal cancer and possibly cervical cancer138. Additionally, hazelnuts contain fibers which have various effects on the gastrointestinal system and can potentially reduce the risk of cancer. A high intake of dietetic fibers increases the volume of faeces and anaerobic fermentation and reduces the length of intestinal transit. Therefore, the intestinal mucosa is exposed to carcinogens for less time and, because the faecal volume is greater, the carcinogens in the colon are diluted138. Hazelnuts have also a relatively high content of monounsaturated fatty acids (MUFA) and a low content of saturated fatty acids (SFA). A high intake of MUFA and a high MUFA/SFA ratio is one of the typical components of the Mediterranean diet pattern, which has been associated to the anti-cancer activity (low risk of some types of cancer particularly colorectal, breast and prostate) of the Mediterranean diet consume138. The effect of food factors on health status has been recognized since antiquity. More recently, epidemiological studies have led to fundamental research for unraveling the chemistry and mechanism of action of dietary phytochemicals and bioactive compounds. Functional foods and natural health products encompass a wide range of food and ingredients, with a variety of bioactive components responsible for their efficacy in health promotion and disease prevention. Hazelnuts with their various activities can be considered as an excellent and readily available natural product containing multi-target anti-cancer compounds (Figure 8).

Figure 8. Major anti-cancer mechanisms regulated by some of the most important constituents of hazelnuts.

2.8 Hot Pepper

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a homovanillic acid derivative, is the major bioactive pungent compound in hot pepper (Capsicum annum). It has been extensively studied for different properties such as anti-inflammatory143, anti-cancer144, analgesic145, 146, anti-oxidant147 and anti-obesity148 activities. In capsaicin exhibits strong anti-cancer activity through targeting multiple signaling pathways and cancer-associated genes in different tumor stages including initiation, promotion, progression, and metastasis. In fact, literature data have reported that capsaicin decreases cancer cell growth, arrests the cell cycle and triggers programmed cell death in different cell lines, such as cutaneous cell carcinoma, adenocarcinoma, breast cancer, colon cancer, cutaneous cell carcinoma, esophageal carcinoma, gastric cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, nasopharyngeal carcinoma, prostate cancer, and others149, 150. As shown in Figure 9, the anti-cancer mechanisms of capsaicin include activation of apoptosis, cell-growth arrest and inhibition of angiogenesis and metastasis. It stimulates the anti-tumorigenic/tumor-suppressive signaling pathway and related transcription factors, whereas it inhibits oncogenic signaling pathways and tumor promoters. Several anti-cancer mechanisms of the capsaicin are summarized in Table 2.

Figure 9. The anti-cancer mechanisms of capsaicin.

Table 2. The Anti-cancer mechanisms of capsaicin in different types of cancer.

Capsaicin has been shown to induce apoptosis in several types of cancer cells, leaving normal cells unharmed144, 161, 173, 174. As shown by Bley et al. 144 capsaicin induces apoptosis in over 40 cancer cell lines such as esophageal151, pancreatic174, colonic175, liver176, prostatic177, lung178, bladder179 cells, and others. It has been shown to have activity versus different proteins involved in the mitochondrial death pathway, in order to begin apoptosis in many cancer cell lines. All mechanisms of capsaicin implicated in apoptosis are reported in Table 2. For example, capsaicin interacts with Transient Receptor Potential Vanilloids (TRPV) 1 in different types of cancer 163, 164, 180 and TRPV6160, 165, giving pro-apoptotic activity. The p53 tumor suppressor is an anti-cancer mechanism, frequently mutated in many carcinomas181. Capsaicin induces p53 phosphorylation at the Ser-15 residue161 and enhances p53 acetylation through down-regulation of sirtuin 1162, responsible for activation of apoptosis. Conversely, Mori et al. have found that capsaicin induces apoptosis in a p53-independent manner177. Capsaicin increases expression of p53 and phosphorylation at Ser-15, -20 and -392 in the treatment of urothelial cancer, with increased apoptosis164. Deregulation of β-catenin-dependent signaling is a significant event in the development of cancer. The β-catenin is constitutively active in different types of cancer. A study has reported that capsaicin down-regulated β-catenin transcription inducing apoptosis of colorectal cancer cells152. In addition, in another study it has been found that capsaicin increases the cell death with other pro-apoptotic mechanisms including AMP-activated protein kinase, reactive oxygen species161, 172, 182, prohibitin 2183, fatty acid synthase172. All these studies support the hypothesis that capsaicin induces apoptosis of cancer cells with activation of multiple pathways. Several data show that capsaicin may halt growth and division of cancer cells with many mechanisms. For example, different studies have reported that treatment with capsaicin inhibits CDK2, CDK4, and CDK6, inducing G0/G1 cell-cycle arrest in human esophageal and bladder151, 153. Capsaicin interferes with angiogenic signaling pathways and has the potential to prevent malignant cancer. Treatment with capsaicin suppresses VEGF-induced proliferation, migration and tube formation. This compound reduces VEGFR and increases hypoxia-inducible factor 1α (HIF-1α), highlighting important anti-angiogenic properties156, 184. Capsaicin shows anti-invasive and anti-migratory activity, suppressing advanced steps of cancer and reducing metastatic burden16, 185. It inhibits the migration of melanoma cells, thanks to down-regulation of PI3K signaling cascade as well as a reduction in RAS-related c3 botulinum toxin substrate 1 (RAC1)186. In human fibrosarcoma, capsaicin inhibits the EGF-induced invasion and migration of cells with down-regulation of AKT/FAK, extracellular signal-regulated kinases, and p38 MAPK signaling and with down-regulation of MMP9158, 187. Luqman et al. investigated the effect of capsaicin and of capsazepine, its synthetic analog, on NF-B activation using stably transfected 293/NFB-Luc human embryonic kidney cells induced by treatment with TNF-α and on aromatase activity. Moreover, computer-aided molecular docking studies explained the good binding affinity of vanilloids with aromatase and NF-B. In particular, the amino acids Ser299 and Ile278 (H-bond 2.81 Å) resulted the highly conserved residues for capsaicin and capsazepine binding in NF-B p50 site, while Ser6, Arg82, Val86, Arg90 (H-bond 2.89 Å), Gly4, and Ser2 (H-bond 2.81 Å) were analyzed in NF-B p100. B. The most important residues for capsaicin and capsazepine binding with aromatase were the amino acids Trp224, Arg435, and Val373 (Hbond 2.80 Å).188

In conclusion, all these studies show that capsaicin is involved in cancer cell survival, growth arrest, angiogenesis and metastasis. For these reasons, it could be considered as a new possible multitarget cancer therapy candidate.

2.9 Pomegranate

The pomegranate (Punica granatum) is a plant belonging to Punicaceae family which comes from the Middle East, the Mediterranean area, the Eastward and the American Southwest189 . The pomegranate is a small tree or shrub and its fruit possesses therapeutically important constituents, varying slightly in different parts of the fruit itself189, 190.

The fruit is delimited by a leathery pericarp, contained within are numerous arils, each a single seed surrounded by a translucent juice containing sac. Thin acrid-tasting membranes extend into the interior of the fruit from the pericarp, providing a latticework for suspending the arils. The fruit is composed of three parts: the seeds that are about 3% of the weight of the fruit containing about 20% oil; the juice which is about 30% of the fruit weight and the peels or pericarp which also include the interior network of membranes. Other useful parts of the plant include the roots, bark, leaves and flowers. Each part of pomegranate has interesting pharmacologic activity. The phytochemistry and pharmacological actions of all pomegranate components suggest a wide range of clinical applications such as for the treatment and for the prevention of cancer, as well as other diseases where chronic inflammation plays an essential etiologic role189. In particular, the pomegranate fruit consists of the outer peel, which encloses inner seeds and arils. The peel is a useful source of phytochemicals such as proanthocyanidin, phenolics compounds, ellagitannins (ETs), complex polysaccharides, flavonoids and many minerals. Each arils is constituted for the 85% of water, for the 10% of sugar, especially fructose and glucose, and for the 1.5% of pectin, organic acids like ascorbic acid, citric acid and malic acid and bioactive constituents such as phenolics compounds and flavonoids mainly anthocyanin. The seed are composed for the 12–20% of total seed weight by the Pomegranate Seed Oil (PSO). The oil consists of conjugated octadecatrienoic fatty acids. The fatty acid component of PSO comprises over 95% of the oil, of which the 99% is triacylglycerols and polyunsaturated fatty acids such as linolenic acid, punicic acid, oleic acid, stearic acid and palmitic acid. Minor components of the oil include sterols, steroids, and a key component of mammalian myelin sheaths the cerebroside. Moreover, the seeds possess proteins, crude fibers, lipids, vitamins, minerals, pectin, sugars, polyphenols, isoflavones especially genistein, the phytoestrogen coumestrol and the sex steroid, estrone. The seed coat contains delphinidin-3-glucoside, cyanidin-3-glucoside, delphinidin-3,5-diglucoside, cyanidin-3,5-diglucoside, pelargonidin-3,5-diglucoside and pelargonidin-3-glucoside, meanwhile the seed matrix is constituted of lignins, fusion products of cell wall components and hydroxycinnamic acids, and potently anti-oxidant lignin derivatives. The juice is composed by anthocyanins, potent anti-oxidant flavonoids that provide pomegranate juice with its brilliant color, the juice also contains some minerals such as Fe2+. The peel contains both flavonoids and tannins. The leaves contain glycosides of apigenin, a flavone with progestinic and anxiolytic properties and tannins189. Juice and peels possess potent antioxidant properties, while juice, peel and oil are all weakly estrogenic and heuristically of interest for the treatment of menopausal symptoms. The different components of juice, peel and oil are able to interfere with tumor cell proliferation, cell cycle, invasion and angiogenesis showing an anti-cancer activity. The pomegranate chemical complexity is associated with different anti-cancer mechanisms such the increasing of the apoptosis, the decrease of inflammation, the decrease of metastasis and invasion, as well as a decrease in drug resistance189. Other anti-cancer mechanisms associated to the activity of the wide variety of components contained in the pomegranate, are the decrease of the tumor cell invasion through the inhibition of selected metalloproteinase activity and the decrease of focal adhesion kinase activity (Figure 10).

Figure 10. Major anti-cancer mechanisms regulated by some of the most important constituents of pomegranate.

In particular, the ursolic acid, the -tocopherol, the ellagic acid, the quercetin, the ellagitannins, the luteolin and the apigenin compounds are associated with the induction of tumor cell apoptosis. This is due to a decline in activation of NF-B, a decrease in fatty acid synthase activity and tumor necrosis factor, increased caspase activities and upregulation of p21 and p53 expression. The catechins are key pomegranate components able to reduce the drug resistance through interaction with p-glycoprotein expression. Among the bioactive compounds in the pomegranate, are present a peculiar group of polyphenols named Punicalagins, which possess health benefits. The punicalagin is a hydrolysable ellagitannin (ET), these anti-oxidant compound are metabolized in the intestine releasing ellagic acid (EA) into the systemic circulation190. The intestinal normal bacterial flora metabolizes these hydrolysable ellagitannins into smaller molecules, namely Urolithins, which possess an important anti-oxidant activity. So, we can say that due to its composition the pomegranate can be considered a rich source of anti-oxidant and anti-cancer supplements. Pomegranate showed anti-cancer properties in different types of cancer, such as breast, prostate, colorectal, leukemia, bladder, glioblastoma cancer and hepatocellular carcinoma191. In the breast cancer the ellagitannin‐derived compound of pomegranate possessed anti-aromatase activity and are able to prevent the estrogen-responsive tumors; also the pomegranate polyphenols obtained from fermented juice, aqueous pericarp and seed oil inhibit the aromatase activity by 60–80%. In the prostate cancer, the ellagic acid cause cell arrest and reduced cyclin B1 and cyclin D1; the urolithin A induced G2/M arrest, raised cyclin B1 and cdc2 phosphorylation and caused apoptosis in both cell lines. The ellagic acid modulates various microRNAs responsible for colorectal cancer and the polyphenols in pomegranate rind extract suppressed bladder cancer cell EJ proliferation through p53/miR‐34a axis. In the glioblastoma the punicalagin has reduced the U87MG cell viability, has caused apoptosis by the breakage of poly(ADP‐ribose) polymerase (PARP), has caused stimulation of caspase‐9 and caspase‐3, has elevated microtubule‐associated protein light chain 3 II, LC3‐II breakage, has caused green fluorescence–LC3 fusion proteins (GFP–LC3‐II)‐stained punctate pattern in the cells and elevated AMPK/p27 at Thr198 in the cells, which is linked with autophagy cell death. Considerable data demonstrate the in vitro and in vivo efficacy of pomegranate against cancer growth and promotion192, however other studies are needed for a future use of pomegranate as multi-target candidate for various cancer treatment. The anti-proliferative, anti-metastatic and anti-invasive effects of the different components of pomegranate, associated to a remarkable anti-oxidant activity, and the most common hypothesis involving oxidative stress as an inducer in the cancer diseases, are in agreement with a future application of pomegranate for prevention and cure of cancer.

2.10 Rosemary

Rosemary (Rosmarinus officinalis L.) is an aromatic, evergreen shrub plant belonging to the Labiatae family and indigenous to the Mediterranean region and South America193. The fresh and dried leaves have been extensively used as seasoning as well as in traditional medicine194. Recently, rosemary extracts standardized to diterpenes have been approved by the European Union (EU) and given a GRAS (Generally Recognized as Safe) status in the United States by the FDA. Incorporation of rosemary into our food system and through dietary selection (e.g. Mediterranean Diet) has increased the likelihood of exposure to diterpenes in rosemary. In consideration of this, a more thorough understanding of rosemary diterpenes is needed to understand its potential for a positive impact on human health. Three agents, in particular, have received the most attention that includes carnosic acid, carnosol, and rosmanol with promising results of multi target anti-cancer activity (Figure 11) 193.

Figure 11. 2D structures of the major components of Rosmarinus officinalis with a multi-target anti-cancer profile.

Carnosic acid was first discovered by Linde in sage (Salvia officinalis L.)195, then by Wenkert et al.196 in Rosmarinus officinalis L. leaves. Despite the fact that rosemary is used since ancient times for their therapeutic properties, the exploration of the mechanisms of carnosic acid action began only in the early 2000s. Over the last decade, several research teams explored the pharmacological properties of carnosic acid, showing that this molecule may have clinical applications for different human diseases, including cancer (Table 3). Being one of the most potent anti-oxidant agents of rosemary, carnosic acid is known to exhibit effective anti-cancer activity against various cancer cell lines derived from human leukemia, breast, prostate, lung and liver malignant tissues at different half maximal inhibitory197.

Table 3. Molecular mechanisms involved in the anti-cancer effect of carnosic acid.

Carnosol is a derivative of carnosic acid containing a lactone ring first isolated in 1942 from sage, its chemical structure was elucidated by Brieskorn et al. in the year 1964204. Carnosol possesses numerous pharmacological properties including anti-inflammatory, anti-oxidant and antitumor activities. Present findings have been shown the efficacy of carnosol in cancer treatment and prevention. Carnosol has been shown to target multiple pathways associated with inflammation and cancer, which include nuclear factor kappa B (NF-κB), apoptosis-related proteins, androgen and estrogen receptors and antiangiogenic activity. Essentially, carnosol inhibits cancer by promoting apoptosis and inhibiting the cell division cycle (Table 4). In conclusion, carnosol may be effective as an antitumor agent in different types of cancer. However, clinical trial studies are needed to verify the antitumor effects of carnosol in human205.

Table 4. Molecular mechanisms involved in the anti-cancer effect of carnosol.

Rosmanol, a phenolic diterpene was first isolated from the leaves of rosemary by Inatani et al. in the year 1982219. Ethanol extract of rosemary leaves contains less than 0.5% rosmanol, which can be increased by further thermal or oxidative treatment. In a study carried out by Cheng et al., rosmanol has appeared to be the more potent than carnosic acid and carnosol at inhibiting the growth of COLO 205 human colorectal adenocarcinoma cells. Thus, they have explored the molecular mechanism of rosmanol-induced apoptosis in COLO 205 cells. In particular, when treated with 50 μM of rosmanol for 24 h, COLO 205 cells displayed a strong apoptosis-inducing response with a 51% apoptotic ratio (IC50 42 μM). Rosmanol has increased the expression of Fas and FasL, it has led to the cleavage and activation of pro-caspase-8 and Bid, and it has mobilized Bax from the cytosol into mitochondria. The mutual activation between tBid and Bad has decreased the mitochondrial membrane potential and has released cytochrome c and apoptosis-inducing factor (AIF) to cytosol. In turn, cytochrome c has induced the processing of pro-caspase-9 and pro-caspase-3, followed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and DNA fragmentation factor (DFF-45). These results have shown that the rosmanol-induced apoptosis in COLO 205 cells involve the caspase activation and complicated regulation of both the mitochondrial apoptotic pathway and death receptor pathway220. Besides inhibiting tumor development, rosmanol also possesses strong anti-inflammatory properties. Inflammation has been linked to several human cancers and transcription factor NF-ĸB plays a central role in the transformation of inflammation to cancer221. Lai et al., have demonstrated that rosmanol down-regulated iNOS and COX-2 expression via multiple pathways including inhibition of STAT3 and C/EBP proteins and inhibiting NF-ĸB activity by blocking the activation of upstream kinases PI3/Akt/IKK and p38 and ERK1/2 MAPK kinases222.

2.11 Citrus species

Citrus species (C. sp.), belonging to the family of Rutaceae, are one example of natural products containing promising phytochemicals in cancer therapy. In the Mediterranean basin, C. sp. Found favorable climatic conditions leading to extensive cultivation and to the origin of many new hybrids. C. sp. (fruits, leaves) are traditionally used for anti-cancer applications in India and other countries. Citrus fruits (CF) are the most eaten fruits in the MD whose capability to reduce the risk of degenerative diseases and cancer is known223. CF represents one of the most important dietary sources of flavonoid endowed with many biological properties, such as the well-known anti-oxidant activity and the modulation of intracellular key pathways involved in degenerative processes leading to chronic pathologies such as cancer. In particular, dietary flavonoids interfere with carcinogen activation, stimulate carcinogen detoxification, scavenge free radical species, control cell-cycle progression, induce apoptosis, inhibit cell proliferation, oncogene activity, angiogenesis, and metastasis as well as inhibit hormones or growth-factor activity224. More than 8000 compounds with a flavonoid structure have been identified. This large number arises from the various combinations of multiple hydroxyl, methoxyl, and O-glycoside group substituents on the basic benzo-γ-pyrone (C6-C3-C6)225. Four types of flavonoids (flavanones, flavones, flavonols, and anthocyanins, the last only in blood oranges) occur in C. sp and including the flavanone glycosides (mainly di- and tri-O-glycosides), the flavone glycosides (mainly di- and tri-O-glycosides and C-glycosides), and the polymethoxyflavones. Among the C. sp, the O-glycosides occur primarily as either rutinosides or as neohesperidosides. The rutinosides, such as hesperidin, narirutin, eriocitrin, and diosmin occur mainly in orange (C. sinensis) and tangerine (C. reticulata), whereas the neohesperidosides, naringin, neodiosmin, and neohesperidin occur mainly in grapefruit (C. aradise). Lemon (C. limon) is distinguished by glycosides of different flavonols, including isorhamnetin, luteolin, limocitrin, kaempferol and limocitrol. The mains chemical structures of different flavonoids content in C. sp. Are reported in the table 5 226. The concentration of these compounds depends on the age of the plant, and other important factors. Flavonoids may act in the different development stages of malignant tumors by protecting DNA against oxidative damage, inactivating carcinogens, inhibiting the expression of the mutagenic genes and enzymes responsible for activating procarcinogenic substances, and activating the systems responsible for xenobiotic detoxification227. Thus, different C. sp may be used to treat cancer disease through a multi-target activity with better efficacy and decreased adverse effects.

Table 5. Main chemical structures of C. sp flavonoids.

In the tumor microenvironment, from cancer cells initiation to the promotion and eventually progression, compelling evidence indicates the potential activities of flavonoids inhibiting oncogenesis, proliferation, neovascularization, and metastasis and inducing apoptosis. Figure 12 schematizes the main anti-carcinogenic pathways of citrus flavonoids.

Figure 12. The main effects of polymethoxyflavones through angiogenesis, cell cycle regulation, migration and apoptosis.

Regarding the mechanisms of suppression of proliferation and apoptosis, different flavonoids appear to show antiproliferative effects in many kinds of cancerous cell lines. It has been reported that C. sp flavonoids (tangeretin, nobiletin, quercetin, and taxifolin) have anti-proliferative effects on squamous cell carcinoma HTB43. Flavonoids also have shown inhibitory effects on the growth of leukemia HL-60 cells, with an IC50 ranging from 10 to 940 ng/ml in a non-toxic mechanism228, which is almost equivalent to the effects of currently used anti-cancer agents. Flavonoids have been shown to inhibit several kinases involved in signal transduction, such as protein kinases C, tyrosine kinases, PI 3-kinases or S6 Kinase229. Casagrande and Darbon have demonstrated that a C ring with an oxo function at position 4, a C2-C3 double bond and a catechol group at the 3’- and 4’- position was required for maximal inhibition of CDK1 and CDK2230. Interestingly, a similar structure requirement has been demonstrated with regard to the inhibition of PKC and PI3K. Indeed, it has been shown that the tangeretin is able to induce G1 arrest in colorectal carcinoma by the inhibition of CDK2 and CDK4 in a dose-dependent manner231. Tangeretin also has increased the content of the CDK inhibitors p21 and p27 protein and this effect has correlated with an increase in p53 levels. Crude methanol extracts of the peels of Citrus aurantium L. has induced caspase-dependent apoptosis through Akt pathway by inhibiting expression of XIAP and Bcl-2 which are anti-apoptotic proteins, providing the fact that they have anti-carcinogenic activity on human leukemia cells232. Hesperetin, has been reported to possess potent beneficial role against DMH-induced colon carcinogenesis, by inhibiting cell proliferation and angiogenesis and by inducing apoptosis in cancer cells.233 In order to investigate the molecular mechanisms, underlying triggering of apoptosis by hesperetin in silico and in vitro methods were used. The in silico method has been based on the mechanism of binding of hesperetin with NF-kB and other apoptotic proteins like BAX, BAD, BCL2 and BCLXL. In vitro studies were also carried out to evaluate the potency of hesperetin in inducing apoptosis using the human prostate cancer PC-3 cell line. Molecular docking study revealed the interaction of hesperetin with the active site of target proteins FADD, BCLXL, BAX, BAD, BCL2 and NF-kB. All the protein–ligand complexes possessed multiple hydrogen bonds, demonstrating the potential multi-target activity of this compound. On the basis of the ligand binding affinity (G-score) calculated by the Glide software using the SP algorithm, with respect to the other target, Hesperetin was able to exhibit high-affinity binding (-7.48 kcal/mol) thanks to the greater intermolecular forces between the ligand and its receptor NF-𝜅B. In vitro analysis using MTT assay confirmed that hesperetin reduced cell proliferation (IC50 values of 90 and 40μM at 24 and 48h respectively) in PC-3 cells.234 In another leukemia cell line NALM-6, hesperidin, as the glycoside of hesperetin, has promoted apoptosis via conducting the expression of p53 and peroxisome proliferator-activated receptor gamma (PPAR-𝛾) and suppressing the activation of NF-𝜅B235. In human colon cancer cells, 5-hydroxy polymethoxyflavones (5OH-PMFs), induce cellular apoptosis in human colon cancer cells by p53-dependent mechanisms236. Similarly, hesperetin has a potential effect on the proliferation of cancer cell in vivo. For colon cancer model in rats, it has exerted a significant inhibitory effect on proliferating cell nuclear antigen in ACF. Moreover, hesperetin has inhibited the growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice by reducing cyclin D1, CDK4, and Bcl-x, while up-regulating the level of p57Kip2237. Tangeretin has been observed to have the lowest IC50 value on COLO 205 human colon carcinoma cells by triggering apoptosis and increasing p53 expression. It also was able to induce apoptosis on HL-60 human promyelocytic leukemia cells238. While nobiletin has been observed to be cytotoxic not only through modulating cell cycle, but also by inducing apoptosis on TMK-1, MKN-45, MKN-74, and KATO-III human gastric carcinoma cells239. At a concentration of 40 and 80 μM hesperetin has showed cytotoxic activity and could activate caspase 3 on HL-60 cells stronger than hesperidin. Naringenin has induced apoptosis via p53 independent pathway on KATOIII and MKN-7 gastric cancer cells and HepG2, Hep3B and Huh7 liver cancer cells and also via intrinsic pathway by down-regulation of Bcl-2 and up-regulation of Bax, caspase-3 activation and PARP cleavage on THP-1 leukemia cells240. Hesperidin has increased wild type p53 expression and induced apoptosis in A549 lung adenocarcinoma, MCF-7 breast adenocarcinoma and NALM-6 leukemia cell lines. Hesperetin has showed similar effects in wild type p53 expression and apoptosis in the SiHa cervical carcinoma cell line241. Concerning the anti-angiogenesis activity, in vitro and in vivo investigations have indicated that some citrus flavonoids are able to inhibit several key events of the angiogenic process such as the proliferation and migration of endothelial cells and vascular smooth muscle cells; the expression of two major pro-angiogenic factors VEGF and MMP-2240. A derivative of naringin, the 8-prenylnaringenin inhibits angiogenesis induced by basic fibroblast growth factor (bFGF), VEGF, or the synergistic effect of the two cytokines, with an IC50 between 3 and 10 μM242. Several in silico studies have been conducted to observe tangeretin and nobiletin’s binding on certain proteins involved in the angiogenic activity. These studies have proved that their mechanism of action in inducing angiogenesis, is due to the recognition of ERK-2 and HIF1-α proteins, respectively243. In addition, the chemopreventative effects of flavonoids are closely linked to their capacity to the scavenge reactive oxygen species and to reduce the growth promoting oxidants, which are the major catalysts for tumor promotion. The propensity of a flavonoid to inhibit free radical-mediated events is governed by its chemical structure. Specific structural elements of the flavonoids determinate anti-oxidant activity of these compounds. Free radical scavenging capacity is primarily attributed to the high reactivity of hydroxyl substituents237. Flavonols and flavanols with a 3-OH group both have planarity, which increased flavonoid phenoxyl radical stability244. Furthermore, methoxy groups introduce unfavorable steric effects and increase lipophilicity and membrane partitioning. C. aurantiifolia extract, containing hesperidin as the most dominant flavonoid, has shown radical scavenging activity245. It also has been demonstrated, by using electron spin resonance spectrophotometer, that hesperidin is moderately active as anti-oxidant246. Hesperidin, nobiletin, and tangeretin have showed anti-oxidant activity in various anti-oxidant assays in vitro247. Some citrus flavonoids are also effective in cell cycle arrest. In particular, hesperetin, one of the most prevalent flavonoids, has repressed CDK2, CDK4, and cyclin D and simultaneously has enhanced p21 and p27 expression to block cell cycle in G1 phase237. In human breast and colon cancer cells, both tangeretin and nobiletin have inhibited the proliferation and have led to the accumulation of cells in the G1/S cell cycle. An in vivo study has shown that besides suppressing c-Myc expression, C. reticulata peels ethanolic extract with the dosage of 500 mg/kgBW might reduce the number of cells expressing N-Ras in DMBA-induced rats’ hepatic carcinogenesis243 and its suppression of c-Myc expression as well. Molecular docking of nobiletin and tangeretin on CYP1A2 (isoenzyme of cytochrome P-450 that is able to activate procarcinogenic substance, benzo[A]pyrene) has displayed that tangeretin binds CYP1A2 stronger than α-naphthoflavone, while nobiletin does not. Hesperetin has manifested anti-cancer activity on MCF-7 cells through cell accumulation at G1 phase by inhibiting the expression of CDK2, CDK4 and Cyclin D; increasing the expression of p21 and p27; and increasing the binding of CDK4 and p21, but not p27 or p57248. An in vitro study demonstrated that tangeretin alone has induced G1 arrest by increasing the expression of CDK inhibitors p37 and p21 in COLO 205 human colon carcinoma cells231. It has been observed that nobiletin explicates cytotoxic activity by modulating cell cycle on TMK-1, MKN-45, MKN-74, and KATO-III human gastric carcinoma cells239. Another study has indicated that the compound induced G1 phase arrest on MDA-MB-435, MCF-7, and HT-29 cells249. Whilst naringin, a glycoside form of naringenin, has inhibited proliferation bladder cancer cells and has induced G1 arrest by up-regulation of p21250.

CONCLUSION

Since the incidence of cancer in the world is constantly increasing, there is an urgent need to discover new anti-cancer drugs. Several medicines are available in the treatment of different types of cancer, unfortunately, no drug has proved fully efficient and safe. The main problem is due to the toxicity of the known drugs. However, natural products have always been an important and conspicuous source of bioactive compounds in cancer treatment. In particular, in the Mediterranean diet many components, such as flavonoids, phenolic alcohol, phenolic acids, squalene, lignans, have been associated with a reduced risk of developing multifactorial diseases, as the cancer. For these reasons, in this review, we have collected the individual Mediterranean components, thus highlighting its different implications and its role as a multi-target source in the prevention and treatment of cancer. Therefore, we reported the properties of these bioactive compounds, describing the anti-cancer effect on the main pathways involved in the different stages of tumor development.

ASSOCIATED CONTENT

Author Contributions

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

AUTHOR INFORMATION

Corresponding Author:

*E-mail: rocca@unicz.it

ACKNOWLEDGMENTS

This Article is based upon work from COST Action CA15135, supported by COST. The authors acknowledge the PRIN 2017 research project “Novel anticancer agents endowed with multi-targeting mechanism of action” (201744BN5T).

ABBREVIATIONS

Reactive oxygen species (ROS); Tumor necrosis factor receptors (TNFRs); Food and Drug Administration (FDA); Mediterranean diet (MD); Extra-Virgin Olive Oil (EVOO); Tyrosol (TY); Hydroxytyrosol (HT); Oleuropein (OL); Estrogen receptor (ER); T24 Human Bladder Cancer Cells (T24-HBCC); Glycogen synthase kinase-3β (GSK-3β); Extracellular-signal-regulated kinases (ERK); Vascular endothelial growth factor (VEGF); 1,2-dimethylhydrazine (DMH); Oral squamous cell carcinoma (OSCC); Cyclin-dependent kinase (CDK); Interleukin (IL); Prostaglandin E2 (PGE2); Tumor necrosis factor α (TNF-α); Interferon (INF); Proliferator-activated receptor (PPAR); Nuclear factor kappa-B (NF-κB); Activator protein (AP); Urinary plasminogen activator (u-PA); Epithelial-mesenchymal transition (EMT); Cancer stem cells (CSCs); Dihydrotestosterone (DHT); Organsulfur compounds (OSCs); Diallyl sulfide (DAS); Diallyl disulfide (DADS); Diallyl trisulfide (DATS); transmission electron microscopy (TEM); Anti-apoptotic (Bcl-2); Monounsaturated fatty acids (MUFA); Transient Receptor Potential Vanilloids (TRPV); Hypoxia-inducible factor 1α (HIF-1α); Botulinum toxin substrate 1 (RAC1); Ellagitannins (ETs); Pomegranate Seed Oil (PSO); Ellagic acid (EA); Poly(ADP‐ribose) polymerase (PARP); European Union (EU); DNA fragmentation factor (DFF-45); Citrus fruits (CF); 5-hydroxy polymethoxyflavones (5OH-PMFs); Peroxisome proliferator-activated receptor gamma (PPAR 𝛾); basic fibroblast growth factor (bFGF); Vascular endothelial growth factor (VEGF); Extracellular-signal-regulated kinases (ERK); Nuclear factor kappa-B (NF-κB).

Conflict of interest

The authors declare no conflicts of interest

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