## 2 Pomergnate Health-Promoting Properties
### Anticancer Properties
[56] have demonstrated that ellagic acid and its secondary products can contribute to the prevention of colon cancer by regulating the expression of multiple genes implicated in crucial processes linked to the development of cancer. Another tannin, the punicalagin (9), is present almost exclusively in the skin. It has several pharmacological properties, among which are anti-inflammatory, anti-proliferative, pro-apoptotic, and anti-genotoxic [57]. It also induces apoptosis in colon cancer cells (cell lines: HT-29, HCT116) and prostate cancer cells at a concentration of 100 mg/mL [5]. A study with 46 patients with prostate cancer under experimentation showed, for 16 of them, a considerable decrease in PSA (prostate-specific antigen) during treatment with pomegranate juice [58]. [PERSON] et al. [59] report that treatment of LAPC4 prostate cancer cells with 10 mg/mL pomegranate extract, obtained from seedless arils and skin, and standardized to a 37% ellagitannin content in punicalagin, blocks cell proliferation and triggers apoptosis. Furthermore, pomegranate skin extract (PoPx) with a high concentration of ellagitannins provokes apoptosis in human breast cancer cells (MCF-7), estrogen receptor (ER)-positive (ER+). In previous investigations, PoPx and genistein have shown significant inhibitory effects on the proliferation of breast cancer cells MCF-7. In addition, PoPx can impede cell proliferation and the expression of angiogenesis markers, phosphorylation of p38, and C-Jun protein kinases activated by mitogens, and the activation of pro-survival signaling pathways. PoPx inhibits the nuclear factor NF-kB gene expression, connected with proliferation, invasion, and motility in aggressive breast cancer phenotypes [60]. [PERSON] et al. reported that treatment at a dose of 300 mg/mL of pomegranate fruit extract (PoMx) in combination with 1 mM tamoxifen is able to reverse the resistance [61]. Moreover, recently [PERSON] et al. identified PoMx as an interesting agent to cope up with oral cancer metastasis. Indeed, it was able to block wound healing migration, transwell migration, and matrix gel invasion. Analyzing the molecular mechanism, they also demonstrated that PoMx was able to downregulate matrix metalloproteinase MMP-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling in HSC-3 cells [62]. PoPx prevent melanocyte proliferation and melanin synthesis by suppressing tyrosinase activity (IC\({}_{50}\) = 182.2 mg/mL). The amount of inhibition is comparable to arbutin, a glycoside with isoquinoline structure capable of being hydrolyzed in glucose and hydroquinone. An extensive amount of research has confirmed the ability of PoPx and ellagitannins to block the generation of free radicals in Ultraviolet (UV)A- and B-irradiated human skin, thus defending it from DNA fragmentation, from skin burns and depigmentation [63; 64]. In 2010, [PERSON] et al. reported that pomegranate extract (PE) is able to inhibit in a time- and concentration-dependent manner (already at 10 mg/mL) the viability and proliferation of a mouse mammary cancer cell line (WA-4, resulting from mouse MMTV-Wnt-1 mammary tumors) characterized by the presence of several cells possessing stem cells features. In particular, the arrest of cellular growth in the G0/G1 phase and an increased level of caspase 3 enzyme was observed, suggesting the mechanism of cell death by apoptosis. Further investigations assessed the outcomes of individual phytochemicals derived from PE. Indeed, ellagic acid, ursolic acid (10), and luteolin (11) could contribute to the inhibitory potential of PE, with an IC\({}_{50}\) value of 10 mM. Instead, caffe acid seemed to be inefficient [65]. Subsequently, in 2011, the same research group verified the arrest of cell growth due to PE but in the G2 phase by using as an in vitro model the human pancreatic cells PANC-1 and AsPC-1.