## 5 Pomegranate in the Treatment of Digestive Diseases  
### Pomegranate and Colorectal Cancer  
As mentioned previously, pomegranate has an anti-cancer effect on various types of cancers, including colorectal cancer. The latter is one of the most common cancers diagnosed in both sexes, and it is characterized by uncontrolled proliferation of cells in the colon and rectum [97]. The ellagitannin urolithin A, one of the major constituents of pomegranate, has an important role in the hindering of colon cancer cell proliferation via cell cycle arrest and the hindering of MAPK (mitogen activated protein kinase) signaling [56]. Ellagitannins and urolithin derived from pomegranate juice were found to reduce the presence of CYP1 enzymes, which are involved in the conversion of inactive carcinogens into active carcinogenic chemicals in colon cancer [98]. In an experiment conducted on HT-29, a colon cancer cell line, the pomegranate's extracts were found to inhibit cell proliferation in a dose-dependent manner while excluding non-cancer cells. Pomegranate inhibited TNF-induced COX-2 protein expression, which is frequently expressed in cancer, as well decreased AKT activity, a protein involved in processes related to cell proliferation and survival [99]. Additionally, another study demonstrates how COX-2 selective inhibitor might decrease the proliferation of HT-29 cancer cells. Therefore, it is suggested that one key mechanism behind pomegranate juice's anti-proliferative effects on colon cancer is its ability to modulate COX-2 expression [90]. Furthermore, ellagitannin and urolithin were found to increase apoptosis in cell lines, resulting in a decrease in cell colony size. Both the lipid and aqueous pomegranate fractions appear to have selective apoptotic potential, downregulating cyclins A and B1 and upregulating cyclin E, resulting in S phase cell-cycle arrest and apoptosis via an intrinsic pathway mediated by cytochrome c release from mitochondria into the cytosol [24].Thus, by triggering apoptosis, both of these substances suppressed the growth of HT-29 cells in a time- and dose-dependent manner [98]. Pomegranate's chemopre activity against colon carcinogenesis has been linked to its antioxidant activity. By preventing azoxymethane-induced oxidative stress, pomegranate peel extract was able to decrease the genotoxicity and pre-malignant lesions caused by azoxymethane-induced colon cancer [100; 101]. In addition, pomegranate extract significantly reduced tumor weight and hemoglobin concentrations in chick chorioallantoic membrane (CAM) implanted colon cancers; this suggests that pomegranate has anticancer properties, particularly through inhibition of angiogenesis [102]. In addition, the consumption of oil extracted from pomegranate seed was found to reduce the number of colonic adenocarcinomas [103] (Figure 6). Figure 6: Pomegranate effect in colon cancer. In vivo, several studies were also conducted to examine the anti-cancerous effect of the various components of pomeranate. Based on animal studies on rats that were affected with colon cancer, which caused an increase in antigens specific to colon cancer, it was discovered that pomeranate peel extracts caused a decrease in the cancer-specific parameters that were induced in mice. The in vivo study also suggested that pomeranate is effective in the treatment of colon cancer by inhibiting proliferation and increasing apoptosis, as evidenced the downregulation of \(\beta\)-catenin genes, which play a critical role in the progression of colon cancer [98; 104; 105]. In order to investigate the impact of pomeranate juice on colon cancer, its effect on aberrant cryptic foci (ACF) was examined more precisely. In fact, pomeranate juice significantly decreased the amount of colonic ACF in male rats by 91 percent. In addition, in rats fed pomeranate juice, it was discovered that the number of large crypts had significantly decreased, and these animals had few crypts/ACF that were visible. Another pathway is also included: the Wnt pathway.