Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma

Abstract

⌬9 -Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth (IC 50 between 6.0 and 10.6 M), with significantly lower potency in noncancer cells. The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells. Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB 2 and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca 2ϩ and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.The therapeutic properties of the hemp plant, Cannabis sativa, have been known since antiquity, but the recreational use of its euphoric and other psychoactive effects has restricted for a long time research on its possible pharmaceutical application. The isolation of ⌬ 9 -tetrahydrocannabinol (THC), the main psychoactive component of Cannabis (Gaoni and Mechoulam, 1964), opened the way to further investigations. After the discovery of the two specific molecular targets for THC, CB 1 , and CB 2 (for review, see Pertwee, 1997), it became clear that most of the effects of marijuana in the brain and peripheral tissues were due to activation of these two G-protein-coupled cannabinoid receptors. However, evidence is also accumulating that some pharmacological effects of marijuana are due to Cannabis components different from THC. Indeed, C. sativa contains at least 400 chemical components, of which 66 have been identified to belong to the class of the cannabinoids (Pertwee, 1997).To date, cannabinoids have been successfully used in the treatment of nausea and vomiting (for review, see Robson, This study was supported by GW Pharmaceuticals (research grant to V.D.M.).Article, publication date, and citation information can be found...

Molecular Targets of Cannabidiol in Neurological Disorders

“…The same group used the same approach to assess CBD effects at human TRPV1 expressed in HEK293 cells for a third and final time [71]. Again, some disparity between the results presented and those previously published was evident as CBD's efficacy was consistent with that reported by Ligresti et al [99] but not that reported by Bisogno et al [19]; however, potency differed from both preceding papers (EC 50: 1.0 μM vs 6.3μM ( [71] estimated from Ligresti et al [99] vs 3.5 μM [19]). Taken together, these results suggest that CBD can submaximally activate TRPV1 receptors, although the potency of CBD's effects remains less well defined.…”

“…Notably, other molecular targets of CBD are present in HEK293 cells (e.g., VDAC1; see Tables 1, 2, 3 and 4) but their expression on intracellular membranes is likely to prevent CBD-mediated effects from being identified by an assay such as this. This group used the same approach in a later study that examined anticancer effects of CBD [99], where CBD effects at human TRPV1 expressed in HEK293 cells were again assessed and reported in the same way as above. While specific EC 50 and efficacy results for were not formally presented, an estimate from the concentration-response curves published in suggests that CBD was both less efficacious (~50% vs 70%) and less potent (~6.3 μM vs 3.5 μM) than previously reported [99].…”

“…This group used the same approach in a later study that examined anticancer effects of CBD [99], where CBD effects at human TRPV1 expressed in HEK293 cells were again assessed and reported in the same way as above. While specific EC 50 and efficacy results for were not formally presented, an estimate from the concentration-response curves published in suggests that CBD was both less efficacious (~50% vs 70%) and less potent (~6.3 μM vs 3.5 μM) than previously reported [99]. The same group used the same approach to assess CBD effects at human TRPV1 expressed in HEK293 cells for a third and final time [71].…”

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

“…In this study, two different tumor cell lines transplanted to hairless mice were half as big as those of the untreated group, and both breast-and lung-cancer cells injected to paws showed approximately three times less metastatic invasion. 112 An inhibitor of basic helix-loop-helix transcription factors (Id1) has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. CBD could down-regulate the Id-1 expression in aggressive human breast cancer cells, and the concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells.…”

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells

“…CBD does not have appreciable affinity for CB 1 or CB 2 receptors and does not have psychotropic activities (10). CBD has been shown to inhibit breast cancer metastasis in vivo in mice (11). However, modulation of a distinct signaling pathway that would explain the inhibitory action of CBD on breast cancer metastasis has not been elucidated.…”