## 4 Molecular Effects of _Cannabis sativa_ L.
### Colorectal Cancer  
Normal and cancerous human colorectal tissues express both CB1 and CB2, indicating that cannabinoids have biological effects not only on colon but also on colorectal cancer. In this context, [PERSON] et al. showed that CBD exerts significant antiproliferative effects in Caco-2 and HCT116 colorectal carcinoma cell lines through induction of caspase 3 and apoptosis with an IC50 value reported as 7.5 \(\pm\) 1.3 \(\upmu\)M [132]. The molecular mechanisms underlying such effects are related to multiple pathways, such as mediated by CB(1)-, TRPV1, and PPAR-antagonists sensitive manner [132]. Accordingly, [PERSON] et al. reported that cannabinoid treatments decreased cell viability in undifferentiated Caco-2 cells via CB1 receptor. In comparison to the undifferentiated cells, CaCo-2 differentiated cells did not respond to cannabinoid treatments. It is interesting to note that the overall CB1 expression levels remained unchanged after differentiation [53; 70; 133].  
In line with this study, it was demonstrated that HCT116 and DLD-1 colorectal cancer cells, treated with different concentrations of CBD, present elevated rate of apoptosis at treatment doses as low as 4 \(\upmu\)M [134]; the selectivity of CBD actions have also been proved since no effects have been found in normal primary colorectal CCD-18 Co cells and normal primary lung Beas2B cells. Regarding the mechanisms of death triggered by CBD, it has been shown that it induces Noxa-mediated apoptosis through the generation of ROS and excessive ER stress in both HCT116 and DLD-1 cells [134]. [PERSON] et al. also found that Noxa-activated apoptosis was dependent on excessive ER stress from ATF3 and ATF4 [134]. An additional pathway that, at least in part, contributes to CBD effects, is linked to autophagy-mediated death as well as to the arrest of cell cycle [126]. [PERSON] et al. investigated the effects of CBD on the CT26 colon cancer cell line, showing that the beneficial effects of CBD are due to relevant antioxidant activity mediated by superoxide dismutase (SOD) and glutathione peroxidase (GPX) [1].  
The possible use of phytocannabinoids in combination with different conventional therapies is gaining increased attention. Although oxaliplatin is an effective chemotherapeutic drug CRC treatment, patients often develop resistance to it; NOS3 is an essential molecular target for oxaliplatin resistance. The combinational treatment in vitro of CRC cells with oxaliplatin and CBD is able to decrease NOS3 phosphorylation, resulting in autophagy, and overproduction of ROS, thus overcoming oxaliplatin resistance [135].  
It is relevant to notice that, both THC and CBD are able to restore the increase of the permeability and inflammation of intestinal cells, events typically occurring during the neoplastic process [136; 137]; these THC and CBD effects suggest the regulation of inflammation as an additional mechanism for the anticancer effects. In line with this hypothesis, cytokines levels are significantly reduced by CBD treatment in vitro models of colorectal cancer [138; 139].  
Regarding minor phytocannabinoids, CBG also stimulates apoptosis, ROS production, up-regulates C/EBP homologous protein (CHOP) mRNA, and inhibits cell proliferation in colorectal cancer cells [140]. Similarly, in Caco-2 cells, CBC can inhibit cell growth, but only at a concentration of 30 \(\upmu\)M and CBDV reduces cell viability in a concentration-dependent manner, with an IC\({}_{50}\) of 10 \(\upmu\)M [141].  
Myrcene extracts show significant cytotoxic effects in various tumors including breast carcinoma and colon adenocarcinoma [142] and other cell lines [143; 144]. Similarly, in colon cancer cells, D-limonene suppresses cell viability through the induction of apoptosis via the suppression of the PI3K/Akt pathway [145].