## 3 Natural Products: A New Source of Molecules with Antitumor Activity
### Terpenes
#### 3.3.2 Ginsenosides  
Ginsenosides are a subgroup of bioactive chemical compounds that are found in the root of ginseng, an Asian plant. These substances are used in teas, in the preparation of creams, or capsules. Of all the compounds that make up this subgroup, panaxadiol is one of the most notable for its antitumor action in many types of cancer. In the CRC cell line HCT116, this terpene inhibits cell proliferation (IC\({}_{50}\) lower than 10 uM after 72 h of treatment) by suppressing PD-L1 expression; modulating different cellular pathways such as mTOR, MAPK/ERK, or JAK-STAT; and molecules such as HIF-1\(\alpha\). It has also been observed to decrease VEGF levels to exert antiangiogenic action. This has also been shown in studies that were performed on murine models treating mice at a dose of 30 mg/kg every 2 days for 3 weeks [119,120].  
Another of the best known ginsenosides is Rg3. A study demonstrated that Rg3 was able to inhibit cell proliferation (IC\({}_{50}\) between 100-200 uM after 48 h of treatment) and promote apoptosis in the HT-29 tumor line, decreasing its pluripotency and decreasing its angiogenesis through deregulation of the AMPK molecular pathway [121]. Analysis of its in vivo activity showed that its treatment with 25 mg/kg of Rg3 for 12 consecutive days reduced tumor vascularization and increased the toxicity that was produced by the chemotherapeutics 5-FU and oxaliplatin, allowing evasion of chemoresistance to both drugs [122].  
The study of panaxadiol in the HCT116 cell line resistant to 5-FU has demonstrated the ability to inhibit proliferation producing synergy in combination with this chemotherapeutic compound, stopping the cell cycle and inducing apoptosis. Its sensitizing effect has also been analyzed in mouse models combining 30 mg/kg of 5-FU and 15/30 mg/kg of panaxadiol, confirming the results that were obtained in vitro, where a significant reduction in tumor size has been observed [123]. Another in vitro study demonstrated that panaxadiol was synergistic with irinotecan in HCT116 and SW480 tumor lines [124]. On the other hand, Rg3 showed synergy with 5-FU both in vitro and in vivo in SW620 and LOVO lines, having shown suppression of proliferation and tumor development and metastasis generation through PI3K/Akt activation [125].  
Among all the terpen that were studied, Rg3 has been the most encapsulated in formulations to increase its biological availability. [PERSON] et al. synthesized nanoformulations of Rg3 encapsulated in pH-sensitive poly (ethylene glycol) that increased the blood circulation of the compound showing rapid release and enhanced cytotoxicity against free drug in SW480, SW620, and CL40 tumor cells. Meanwhile, these formulations did not possess toxicity in the non-tumor line CCD-18 Co at the concentrations that were tested. Meanwhile, in vivo experiments showed a greater reduction of tumor volume versus the free compound, increasing apoptosis in the tumor sinus [126]. Finally, [PERSON] et al. synthesized folato-targeted polyethylene glycol nanoparticles based on cyclodext that co-encapsulated Rg3 and quercetin. The microtumor environment modulating effect that was demonstrated by Rg3 together with the oxidative stress inducing ability of quercetin exhibited a high cytotoxic effect on CRC lines CT26 and HCT116. The in vitro effect was reflected in in vivo experiments, where increased survival of mice was shown in combination with an anti-PD-L1 drug [127].  
Rg3 was tested in clinical trials as a possible hepatocellular carcinoma treatment (NCT02724358 and NCT01717066), although it was not tested for CRC therapy as there is no sufficient knowledge of this compound in this type of carcinoma.