## 3 Natural Products: A New Source of Molecules with Antitumor Activity
### Flavonoids
#### 3.2.2 Epigallocatechin Gallate  
Epigallocatechin gallate (EGCG) belongs to the flavanol group and is the most studied compound of this group in CRC. It is found mainly in green tea but is also found in other foods such as pistachios, strawberries, kiwis, hazelnuts, blackberries, and cherries. This compound is characterized by its antimuoral properties, acting as a chemopre agent through the inhibition of carcinogenesis in numerous types of cancer. The mechanisms that are used by this catechin to carry out its antitumor effect are based on the regulation of various signaling pathways that are involved in proliferation, apoptosis, angiogenesis, and metastasis. Among them, EGCG inhibits colonic tumor cell proliferation and migration inducing apoptosis through the activation of caspase-3 and PARP, in addition to produce the downregulation of STAT3. This compound was tested on CRC lines SW480, SW620, and LS411N and IC\({}_{50}\) values of 74.6, 99.4, and 112.1 \(\upmu\)g/mL were obtained after 24 h of treatment, respectively [99; 100].  
Its chemo-sensitizing activity has been studied in CRC cells that are resistant to chemotherapules. The combination of EGCG with 5-FU increases the efficacy of the latter, as well as its cytotoxic action, acting on tumor target cells. This effect has been observed in HCT116 and SW480 cell lines [101; 102]. One of the mechanisms that is used by EGCG to enhance sensitivity to 5-FU is the inhibition of the GRP78/NF-\(\upkappa\)B/miR-155-5p/MDR1 pathway, having been demonstrated in in vitro and in vivo studies [103]. Furthermore, in vivo experiments demonstrated that administration of 30 mg/kg EGCG for two weeks decreased the number of hepatic metastatic lesions, reduced tumor growth, and increased apoptosis in tissues. In addition, less vascularization was found in treated tumors versus controls [104].  
EGCG also has synergistic effects in combination with irinotecan in HCT116 cell lines. It has been observed that this drug produces S- and G2-phase arrest, inducing genotoxicity, an effect that was not observed in cells that were treated with EGCG alone [18]. Cisplatin and oxaliplatin are two chemotherapules that are used in the treatment of CRC. The combination of EGCG with these two agents in DLD-1 and HT-29 cell lines has shown an increased cytotoxic effect, causing cell proliferation inhibition and inducing autophagy [105]. These studies suggest that the combination of EGCG with different chemotherapules in CRC produce a synergism that increases antitumor activity.  
To improve the bioavailability of this compound, [PERSON] et al. synthesized gelatin and chitosan nanoparticles encapsulating 5-FU and EGCG, the latter compound inhibited tumor growth through its anti-angiogenic action and its ability to induce apoptosis. Encapsulation in this formulation allowed both compounds to increase blood circulation time in in vivo experiments, making them effective formulations against CRC [106].  
A clinical trial was carried out with green tea extract, whose main bioactive compound was EGCG, trying to show whether the administration of 150 mg twice a day was able to reduce the risk of CRC, with no significant differences between the treatment group and the placebo [107]. Moreover, the chemo-sensitizing effect of EGCG is a breakthrough in overcoming tumor resistance. However, more evidence is needed to translate these results to clinical assays.