## 3 Natural Products: A New Source of Molecules with Antitumor Activity
### Polyphenols
#### 3.1.2 Curcumin  
On the other hand, curcumin is one of the most studied bioactive compounds as an adjuvant in CRC. This phytochemical is derived from turmeric (_Curcum longa_) and is used as a dietary supplement or food flavoring [66]. The mechanisms by which it influences CRC have been extensively studied. It is known to regulate the microbiome, protect the intestinal barrier and promote anti-inflammatory activity in the intestine through inactivation of the proinflammatory factor NF-\(\kappa\)B and by increasing the expansion of CD4+ FOXP3+ regulatory T lymphocytes in the mucosa. In addition, it modulates tumor cell death via the autophagy mechanism by suppressing the PI3K/AKT/mTOR signaling pathway and it is able to trigger epigenetic modifications that increase its chemosensitizing power together with other drugs [67]. Pharmacokine and toxicity studies showed that its administration in humans is safe, although its absorption is low and it is a compound that is rapidly eliminated by the body, problems that currently prevent it from being tested as a therapeutic agent [68]. The chemopretive action of curcumin in CRC has been demonstrated in numerous in vitro studies. In the HT116 cell line, it inhibits proliferation by blocking the WNT/\(\beta\)-catenin pathway that is mediated by c-MYC, producing cell cycle arrest in G2/M phase, and inducing apoptosis. In the HT-29 cell line, curcumin is also able to stop the cycle in the G1 phase and induce apoptosis by acting on the pAKT-AMPK-COX-2 signaling pathway at a dose of 20 uM [69]. In addition, curcumin has been shown to inhibit the migration and invasion of HT116 and LoVo cell lines [70]. In vivo studies that were conducted in murine models have shown that a dose of 300 mg/kg prevents progression to cancer from precancerous lesions, reducing the number of adenomas and tumor size [71; 72]. Clinical studies that were conducted in humans observed that oral consumption of curcumin in CRC patients reduced serum TNF-\(\alpha\) levels and increased apoptosis in the tumor tissue tested [73]. Curcum has also been studied as an adjuvant and chemosensitizer in combination with drugs that were traditionally used in the treatment of CRC. Several in vitro and in vivo studies have demonstrated the ability of curcumin to decrease tumor cell resistance to drugs such as 5-FU and oxaliplatin. Particularly, in vitro studies indicate that this compound decreases the expression of several genes (IGF-1, AKT, COX-2, and cyclin D1) that are involved in resistance to these two drugs [73]. It has also been shown, in oxaliplatin-resistant HCT116 cell lines that were cultured with this chemotherapeutic and curcumin, that resistance is reversed through inhibition of the TGF-\(\beta\)/SMAD2/SMAD3 pathway. In mice that were transplanted with oxaliplatin-resistant HCT116 cells, the administration of curcumin together with oxaliplatin has also been observed to significantly reduce tumor volume and weight [74]. The combination of a slightly cytotoxic dose of curcumin (10 uM) with 5-FU (5 uM) produced a synergistic antitumor response, reducing cell growth, and inducing apoptosis as observed in in vitro and in vivo studies. This chemo-sensitizing effect is carried out by inhibiting STAT1 activation, which reduces PD-L1 expression [75]. Furthermore, this synergism could also lead to a decrease in CRC progression and metastasis, thanks to the ability of curcumin to decrease the expression of IGF-1 and the myc oncogene [76]. As curcumin is one of the most studied natural compounds, studies have attempted to encapsulate it to increase its bioavailability and absorption. [PERSON] et al. designed a nanoformulation based on fusion proteins that were capable of being efficiently introduced into cells with high expression of epidermal growth factor receptor (EGFR), being more effective in the HCT116 line (EGFR-positive) versus SW620 (EGFR-negative) [77]. [PERSON] et al. encapsulated the compound in micelles and increased its bioavailability and cytotoxic activity in CRC cell lines.