# Antitumor Effects of _Cannabis sativa_ Bioactive Compounds on Colorectal Carcinogenesis
## 3 Bioactive Compounds in the Prevention and Treatment of Colorectal Cancer
### Effects of Terpenes on CRC  
Terpenes have been screened for their potential to prevent CRC when used alone or, in the case of the _C. sativa_ plant, to enhance the plant's medicinal properties. These compounds act by inhibiting the growth and proliferation of cancer cells, and by inducing apoptosis. In addition, there is evidence that some terpenoids may have similar effects to cannabinoids, such as THC, in terms of their ability to interact with the endocannabinoid system. This interaction can cause changes in the activity of certain receptors and enzymes, which in turn affect a wide range of physiological processes. Indeed, \(\beta\)-caryophyllene was shown to interact with the CB2 receptor, acting as its full agonist, resulting in a reduction in pain and inflammation in male rats and mice [71]. Furthermore, in a study conducted by [PERSON] et al., the terpenes \(\alpha\)-humulene, \(\beta\)-pinene, and \(\beta\)-caryophyllene increased the bioactivity of cannabinoids through interaction with the CB1 receptor [72]. One of the most widely studied terpen in the context of CRC is \(\beta\)-caryophyllene (BCP). A study performed by [PERSON] et al. [73] determined that BCP displayed antiproliferative and pro-apoptotic effects on colon cancer cells (HCT116). Treatment with BCP at 20 \(\upmu\)M for 24 h induced a significant suppression of the expression of antiapoptotic proteins, including survivin and X-linked inhibitor of apoptosis protein (XIAP), the serine protease high-temperature requirement factor and a member of heat shock proteins family, HSP60 (\(p<0.001\)). In addition, BCP treatment, at the dose of 200 mg/kg, remarkably reduced the tumor size (0.07%) in an in vivo xenograft model (HCT116 cells). In parallel, the histological analysis of the tumors from the BCP-treated mice revealed a clear reduction in the thickness of the blood vessels compared to untreated tumors. Moreover, BCP was also reported to suppress the activation of signaling pathways involved in cancer development and progression, such as the Akt pathway. A study performed by [PERSON] et al. [74] revealed that BCP (at 50 \(\upmu\)M for 48 h) reduced the levels of p-Akt, p-mTOR, protein 3-phosphoinositide-dependent protein kinase-I, and lactate dehydrogenase A in CT26 cells under high-glucose conditions (\(p<0.05\)). Inflammatory bowel diseases are closely associated with an increased risk of CRC [75]. In this sense, [PERSON] et al. [76] emphasized that the preventive treatment of DSS-induced colitis CD1 mice with BCP (50 mg/kg) resulted in a significant decrease in TNF-\(\alpha\), IL-1\(\beta\), keratinocyte-derived chemokine, and interferon-\(\gamma\) protein levels (\(p<0.05\)) in mice colon segments. These proteins are mediators involved in cellular migration and adhesion. The authors also revealed that the decrease in the inflammatory mediators was associated with the factor nuclear kappa B (NFkB) signaling pathway, as BCP decreased the activation of the p65 NFkB subunit. However, according to the findings above related to CBD and THC, further research should be conducted in cell lines and animal models of CRC to better understand the anti-inflammatory action of BCP in CRC. Indeed, DSS only induces colitis. In animal models of CRC associated with inflammation, DSS is administered with AOM [77]. Furthermore, the combination of terpenes and other drugs was found to provide a synergistic effect in reducing tumor growth in CRC. In this regard, [PERSON] et al. [78] found that the combination of BCP (2.5 and 10 mg/mL) and paclitaxel (0.025 mg/mL) was more effective in inhibiting the growth (17.3 \(\pm\) 0.2%) of CRC DLD-1 cells than the drug applied individually. BCP also increased the cytotoxicity of \(\alpha\)-humulene in breast cancer MCF-7 cells. \(\alpha\)-humulene (32 mg/mL) inhibited cell growth by 50 \(\pm\) 6% alone, and by 75 \(\pm\) 6% when combined with 10 mg/mL of BCP.