## 3 Natural Products: A New Source of Molecules with Antitumor Activity
### Polyphenols
#### 3.1.1 Resveratrol  
Resveratrol is a polyphenol belonging to the stilbenes group. It is found in grapes, blueberries, and peanuts, intervening in the response to infection by microorganisms [47]. From its study it has been determined that it has antioxidant, anti-inflammatory, antitumor, cardioprotective, and neuroprotective properties. These effects are mainly based on its ability to suppress inflammation, regulate various enzymatic processes that are involved in the metabolism of numerous substances, eliminate reactive oxygen species, and inhibit cell proliferation through its action as a phytoestrogen. The therapeutic action of resveratrol comprises different mechanisms such as the induction of cell death through apoptosis and autophagy, the capacity to suppress tumor proliferation, or the inhibition of angiogenesis and metastasis [48]. The preventive and therapeutic effect has also been observed for CRC. In vitro studies that were carried out in different colon cancer cell lines have demonstrated the ability of this compound to inhibit cell growth and proliferation, promoting cell cycle stop and derived apoptosis activating apoptotic markers such as caspases 3 and 8. In the CRC line HT-29, this compound had an IC\({}_{50}\) of 10 mg/mL after 72 h of treatment [49]. Particularly, in HCT116 and CaCo-2 cell lines, it has been observed that resveratrol inhibits cell cycle initiation by the downregulation of the CCND1/CDK4 complex. In addition, resveratrol treatment decreases the synthesis of proangiogenic factors such as VEGF in CRC [50]. Furthermore, it has been observed that it is able to reverse the Warburg effect in tumor cells through modulation of the pyruvate dehydrogenase complex, influencing the process of glycolysis [51]. Its in vivo antitumor capacity has also been shown. Thus, in murine models of rats and mice that had the KRAS proto-oncogene overexpressed, dietary administration of 150 or 300 ppm resveratrol for 4 weeks was shown to prevent tumor growth through the deregulation of KRAS via miR-96 [52]. On the other hand, a model of colonic tumorigenesis in situ showed that resveratrol prevented the formation of precursor lesions (dysplasia or adenomas), in addition to reducing the volume of tumors if they had been generated. The downregulation of the pro-apoptotic gene BAX was observed in the treated tumor mucosa, as well as a reduction of COX-2 and NF-kB [47; 53]. Human clinical trials showed that resveratrol intake was safe and well tolerated systemically, with side effects such as diarrhea, abdominal pain, and nausea being observed in patients that were treated with more than 1 g per day. Despite this, the bioavailability of resveratrol in the body is limited with 71-98% recovery of the compound or its derivatives in urine and feces after oral administration [47; 54; 55]. Another possibility that was studied was the combination of resveratrol together with traditional chemotherapy drugs, showing the sensitization of tumor cells to conventional drugs and the reduction of existing resistance to these drugs. Thus, its combination with 5-FU produced a decrease in cell proliferation and an increase in apoptosis in vitro, accompanied by a reduction in tumor volume and vascular density in vivo [56; 57; 58]. Synergistic effects have also been shown with oxaliplatin, observing that their combination produces a greater inhibition of cell proliferation compared to the chemotherapy alone. The effect of resveratrol is found to be exerted through increased expression of miR-34c, which silences the PI3K/AKT pathway and triggers reduced expression of the resistance gene MDR1 [59]. The death that is produced by this combination is through necrotic and apoptotic pathways [60]. Due to the low bioavailability of resveratrol, formulations have been designed to allow improved transport into the cell. [PERSON] et al.