Cannabidiol, a non-psychoactive cannabinoid compound, inhibits human glioma cell migration and invasiveness

Malignant glioma is the most common primary brain tumor, and its high ability to invade the surrounding brain parenchyma is a leading cause of tumor recurrence and treatment failure. We recently demonstrated that the non-psychoactive cannabinoid compound cannabidiol (CBD) can be effective, both in vitro and in vivo, in limiting tumor cell growth and triggering apoptosis in human glioma cells (1) through an oxidative stress-based mechanism and modulation of LOX pathway and endocannabinoid system (2,3). We were also able to provide the first demonstration of CBD-induced inhibition of cell migration in Boyden chamber assay (4). Since tumor cell motility represents a fundamental aspect in tumor invasion, in the present work we were interested in analyzing further the ability of CBD in inhibiting glioma cell migration and invasiveness. Among the various factors involved in the acquisition of increasing levels of malignancy, matrix metalloproteinases (MMPs) are a group of enzymes that play a pivotal role in promoting tissue breakdown and remodelling during angiogenesis and invasiveness through degradation of extracellular matrix components. Therefore, since MMP-2 is one of the most important MMPs in the spreading of glioma, we investigated the influence of CBD on MMP-2 production and activity. We found that U87 glioma cells exposed in vitro for 24 h to different concentrations of CBD showed a significant inhibition of MMP-2 release in the supernatants of cell cultures, as evaluated by ELISA assay. CBD was also able to alter the MMP-2 gelatinolitic activity, as detected by gelatine zymography analysis. Moreover, using a scratch wound healing assay, we found that the in vitro exposure to CBD for 16 and 24 h, induced a significant inhibition in the rate of glioma cells invasion into the artificial wounded areas. The exposure of U87 cells to CBD also down-regulated signalling pathways critical for cell survival, proliferation and angiogenesis as Akt , ERK and the hypoxia-inducible factor HIF1-. In conclusion, the present investigation adds further insights into the antitumoral action of the non psychoactive CBD, showing multiple mechanisms through which the cannabinoid inhibits glioma cells growth/invasiveness. Considering that CBD is a natural compound without psychotropic and side effects, these data lead us to consider CBD to have high potential as a new anticancer drug alone or in combinatory therapy.