## 4 Molecular Effects of _Cannabis sativa_ L.
### Brain Cancer  
Both CBD and THC are promising compounds in the fight against brain cancers. [PERSON] et al. showed that CBD induces a dose-dependent reduction of both proliferation and viability on glioblastoma multiform (GBM) cancer cells, with a IC50 ranging between 3.1 and 8.5 uM. In addition, co-treatment of CBD with DNA damaging agents produces synergistic anti-proliferating and cell-killing responses in GMB cell line [91]. These data have been confirmed in the U-87 glioblastoma cell line in which CBD led to a concentration-related inhibition of the U87 cell viability [92]. In accordance, [PERSON] et al. analyzed, in the same glioblastoma cell line, the effects of a heterogenous extract from _Cannabis sativa_ L., finding the inhibition of both proliferation and migration from a dose of 25 ug/mL [32]. The underlying molecular mechanism is not completely clear but the authors evidenced DNA damage [32]. Recently, [PERSON] et al. demonstrated that apoptosis together with ROS production are two additional mechanisms involved in CBD inhibitory activity of 3832 and 387 glioma primary stem cell lines (GSC) with an IC50 value of 3.5 uM [93]. The induction of apoptosis has also been confirmed by [PERSON] et al. in neuroblastoma SH-SYSY and IMR-32 cell lines in which a reduction of cancer cell migration and invasion was also induced already with a dose of 10 uM [94]. A recent study suggested a role for CBD in interfering with chemoresistance in glioblastoma cells describing a decrease in prohibitin (PHB) and extracellular vescicles (EVs). EVs are lipid bilayer-enclosed structures which participate in cell-to-cell communication, both in physiological and pathophysiological processes regulating cell migration, differentiation, and angiogenesis and therefore playing an important role in cancers. [PERSON] et al. show that CBD reduces PHB protein levels and changes EV-mediated export of microRNAs to an anti-oncogenic signature in GBM cells [95]. Interestingly, it is to notice that cannabinoid treatment cannot affect cell viability of astrocytes (normal glial cells) in comparison to GBM cells, demonstrating a selectivity towards cancer cells. However, the molecular mechanisms mediating cannabinoid selectivity are not yet fully understood [96; 97]. Regarding THC, similar anti-cancer effects have been demonstrated: [PERSON] et al. found that, in mice and glioma cells, THC inhibits the growth and invasion of gliomasthrough the down-regulation of matrix metalloproteinase (MMP-2 expression), factor involved in the acquisition of invasiveness [98]. The anti-cancer activity of THC on recurrent GBM has also been demonstrated in vivo [99]. The mechanism underlying the THC anticancer properties has been only partially clarified and relies on the stimulation of an ER stress-related signaling pathways that unleash the autophagy-mediated cancer cell death [20; 100]. Whether CBD or THC are more potent in antineoplastic activity on brain cells is still a matter of debate. [PERSON] et al. conducted experiments comparing the two molecules, concluding that CBD is a more potent inhibitor than THC in different glioblastoma cell lines (U87-MG, U251, and SF126) [101]. Besides the use of single cannabinoid, [PERSON] et al. described cannabis extracts as antitumor agents in U-87 MG and T98G glioblastoma cell lines able to impair the survival and proliferation of cancer cells as well as induced apoptosis, to a greater extent than THC alone [102]. In addition, in a combination study, [PERSON] et al. reported that a CBD concentration higher than THC (5:1), in combination with temozolomide [CBD (15 mg/kg) and TMZ (5 mg/kg)], targeted glioma stem cells in vivo much more efficiently than the THC/CBD formulation [103]. Remaining on the evaluation of combinational treatments, [PERSON] et al. demonstrated the upregulation of the cytotoxic effect of \(\gamma\)-irradiation in GBM by the co-treatment with CBD. The dose of CBD treatment ranged between 5 and 20 \(\upmu\)M, in accordance with previous results.