# Antitumor Effects of _Cannabis sativa_ Bioactive Compounds on Colorectal Carcinogenesis
## 3 Bioactive Compounds in the Prevention and Treatment of Colorectal Cancer
### Effects of Cannabinoids in CRC-Associated Mechanisms
#### 3.1.1 Cbd
[53] also proved that phosphatases may also be induced or activated by CBD, namely dual-specificity protein phosphatase 10 (DUSP10), prostatic acid phosphatase (ACPP), and protein tyrosine phosphatase non-receptor type 6 in SW480 cells at 15 \(\upmu\)M. In summary, the previous results suggest that CBD-induced apoptosis can occur through a variety of mechanisms, including the inhibition of the Akt and extracellular signal-regulated kinase (ERK) signaling pathways, which are important for cancer cell survival, as well as the activation of caspase-3, an enzyme involved in the apoptosis process (Figure 5). It is well established that oxidative stress and the generation of ROS are significant factors in apoptosis, and this cellular process can be delayed or prevented by some antioxidants [57]. A study confirmed that CBD caused oxidative stress in HT-29 cells, probably through the generation of ROS, which depleted glutathione (GSH) and inhibited the activities of catalase, glutathione reductase (GR), and glutathione peroxidase (GPx). These findings were supported by the observation that malondialdehydedehyde (MDA) levels were markedly increased (\(p<0.01\)) in cells treated with CBD (2.6 \(\pm\) 0.18 mmol/mL) compared to control cells (1.6 \(\pm\) 0.27 nmol/mL), while they were largely unaltered in HT-29 cells exposed to THC [52]. Combined with oxaliplatin, a chemotherapeutic drug for cancer, CBD (4 \(\upmu\)M CBD for 24 h) also produced similar results in oxaliplatin-resistant DLD-1 and colo205 cells [55]. In contrast, an in vivo study showed that CBD induced a significant increase in the activities of superoxide dismutase, GPx, and GR, and simultaneously decreased MDA levels (\(p<0.05\)) in BALB/c mice (xenograft model, CT26). These events may be linked to other CRC protective mechanisms against inflammation. Indeed, interleukin-6 (IL-6) and IL-8 levels, i.e., pro-inflammatory cytokines, were noticeably lower in the 5 mg/kg CBD-treated groups compared with the CRC groups (\(p<0.05\)) [58]. The anti-inflammatory potential of CBD has already been confirmed in several models of colitis [17]. However, a study carried out by [PERSON] et al. [59] revealed that treatment with purified CBD, at different concentrations (16-252 \(\upmu\)g/mL), resulted in a significant decrease in IL-8 levels at lower concentrations of CBD, while no anti-inflammatory activity was found for the higher CBD concentrations in HCT116 cells. Hence, more research must be undertaken to better understand the anti-inflammatory effects of CBD on CRC. Autophagy and apoptosis are linked and can interact with each other. Autophagy can prevent or delay apoptosis, and apoptosis can also trigger autophagy. Both processes help regulate cell survival and death, contributing to cellular homeostasis maintenance [60]. CBD has also been shown to induce autophagy in oxaliplatin-resistant DLD-1, colo205 cells, and tumor tissues of BALB/c nude mice (xenograft model, colo205) [55]. Microtubule-associated proteins light chain 3 (LC3) and p62 expression, which are commonly used autophagic biomarkers, were both considerably enhanced by the combination of oxaliplatin and CBD in CRC cells. Additionally, the proportion of autophagic cells significantly increased (\(p<0.001\)). In vivo results also revealed a significant increase in microtubule-associated protein LC3 levels in colorectal tumors in oxaliplatin- and CBD-treated mice than in tumors in control mice. This experiment also proved that the cell's response to oxaliplatin was increased when combined with CBD treatment, suggesting that this cannabinoid can be applied in combination with chemotherapeutic drugs in CRC to increase pharmacological effects. Angiogenesis, the recruitment of new blood vessels, is a therapeutic target and an integral component of tumor development, invasion, and metastasis. This process engages a variety of growth factors, including integrins, chemokines, vascular endothelial growth factor (VEGF), and fibroblast growth factor [61]. [PERSON] et al.