Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

Abstract

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC 50 of 25 M. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N- [(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and ␣-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

“…However, in line with our data cannabidiol has been reported to exert several of its effects, including modulation of cytokine release and macrophage chemotaxis [11] as well as antiproliferative [12] and proapoptotic properties [13] in a cannabinoid receptor-dependent manner. One possible explanation for the discrepancy between the low receptor affinity and the apparent involvement of cannabinoid receptors in cannabidiol-mediated effects may be given by cannabidiol´s inhibitory action on fatty acid amidohydrolase activity that confers release of anandamide and increased receptor-mediated signalling by this endocannabinoid [16][17][18].…”

“…Although cannabidiol displays a low affinity to CB 1 and CB 2 receptors [10], several effects of cannabidiol including modulation of cytokine release and macrophage chemotaxis [11], antiproliferative [12] as well as proapoptotic properties [13] have been shown to be mediated via CB 1 and/or CB 2 receptors. In other investigations, cannabidiol has even been reported to display antagonistic effects on CB 1 and CB 2 receptor [14], as well as synergistic effects on THC-mediated hypoactivity, hypothermia and impairment of spatial memory [15].…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…In contrast, when the same in vitro assay was performed on normal fibroblasts (WI-38 human lung fibroblasts) CBD exerted no statistically significant effect on sphingomyelin hydrolysis. Furthermore, the antitumor effect of CBD has been shown to be independent on the production of ceramide in human glioma cells (but was associated with a fall in mitochondrial potential; see below) [83] and thus it remains unclear as to whether or not CBD acts directly on the ceramide pathway. …”

Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action

“…The authors also showed for the first time that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid and vanilloid receptor antagonists. 109 CBD also caused apoptosis in human myeloblastic leukemia cells. 110 In addition, CBD inhibits the migration of U87 human glioma cells in vitro and this effect was also not antagonized by either selective CB 1 or CB 2 receptor antagonists.…”