## 2 Pomergnate Health-Promoting Properties
### Anticancer Properties  
Cancer is the principal cause of death in both developed and developing countries. The mortality rate of this pathology is superior among low and middle-income populations. The higher mortality rates in less well-off countries are mainly due to the lack of adequate health systems [33; 34; 35; 36]. Reactive oxygen species' (ROS) overproduction is held liable to be one of the key factors for the development of several diseases, including cancer. Tumor biology has revealed that most neoplasms have a much higher amount of reactive oxygen species than healthy ones, such as superoxide anion, H\({}_{2}\)O\({}_{2}\), and hydroxyl radicals [37]. These reactive oxygen-containing chemicals react with nucleic acids, proteins, and lipids, contributing significantly to tumor cells proliferation, DNA alterations, apoptosis, metastasis, and angiogenesis [38; 39; 40; 41]. As a consequence of the troubles produced by the existing chemotherapeutic agents, nowadays there is an increasing concern in the search for herbal formulation with cancer preventive effect. Indeed, studies are focusing particularly on fruits rich in polyphenols due to their anticancer potential [42]. In order to investigate the effectiveness of pomegranate and its derivatives as anti-proliferative, anti-invasive, and pro-apoptotic agents, several studies have been conducted on different cell lines, such as breast cancer lines (MCF-7 and MDA-MB-231), uterine cancer lines (HeLa and Ishikawa), colorectal adenocarcinoma lines (RKO), and animal models [43; 44; 45]. Some research groups have shown that the simultaneous use of skin, seed, and pomegranate juice extracts has a synergistic action in inhibiting cell proliferation in several in vitro models, such as: Human breast MCF-7, uterine HeLa, human prostate DU 145, and PC-3 cancer cells. [46; 47]. This result has been confirmed by [PERSON] et al. [48], who demonstrated that pomegranate extracts and juice components have a more potent action than the individual isolated polyphenols, suggesting that it is a synergistic and additive effect of many phytochemical compounds, among which proanthocyanidins, anthocyanins, flavonoids, and ellagitannins. The proanthocyanidins are strong antioxidant compounds that, after acid hydrolysis, can release catechins as (+)-(2R,3S)-catechin (1). They act synergistically with ascorbic acid, which gives therapeutic potential against neoplastic and cardiovascular diseases, since it is able to suppress the action of free radicals, as well as to protect the body from the development and metastasis of cancer (which in part depends on the damage caused to the DNA). The anthocyanins are derivatives of phenyl-4H-benzopyran-4-one and are present in the vacuoles of the epidermal cells of many plants [49]. These are characterized by a high chemical reactivity and very low toxicity. They have, in fact, an anti-free radical action and they modulate the arachidonic acid cascade by inhibiting cAMP-phosphodiesterase [49]. The main anthocyanins present in the pomegranate juice are cyanidin (2), delphinidin (3), and pellargonidine-3-O-glucoside (4). It was shown that anthocyanins decrease the proliferation of colon cancer cells, HT-29, in a dose-dependent manner [5]. The flavonoids, present in the bark and skin responsible for the red color, have a very high antioxidant activity and are useful for blood circulation [50]. The main flavonoids are quercetin (5), which, in addition to an antioxidant action [51], also showed antiviral and cardioprotective effects [52; 53], kaempfer (6), with anticancer properties, and the rutin (7), a molecule with antithrombotic properties [54]. Among the ellagitannins, ellagic acid (8), a highly thermostable molecule, can be extracted from pomegranate skin and possesses important biological activities including antitumor, antiviral, and antimicrobial [55]. In addition, it was shown that ellagic acid (8) induces cell lysis, apoptosis, and thus decreases cell viability due to DNA breakage and alterations in the cell cycle. [PERSON] et al.