⌬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...

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ABSTRACT

Stimulation of cannabinoid CB1 receptors by 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA) inhibits the growth of a rat thyroid cancer cell-derived tumor in athymic mice by inhibiting the activity of the oncogene product p21ras. Here we report that Met-F-AEA also blocks the growth of tumors previously induced in nude mice by the s.c. injection of the same rat thyroid carcinoma cells. Met-F-AEA significantly inhibited, in tumors as well as transformed cells, the expression of the vascular endothelial growth factor, an angiogenetic factor known to be up-regulated by p21ras, as well as of one of its receptors, flt-1/VEGFR-1. The levels of the cyclin-dependent kinase inhibitor p27(kip1), which is down-regulated by p21ras, were instead increased by Met-F-AEA. All these effects were antagonized by the selective CB1 receptor antagonist SR141716A. Met-F-AEA inhibited in vitro the growth of a metastasis-derived thyroid cancer cell line more potently than a primary cancer cell line. Therefore, the hypothesis that CB1 receptor stimulation interferes not only with angiogenesis but also with metastatic processes was tested in a widely used model of metastatic infiltration in vivo, the Lewis lung carcinoma (3LL) in C57Bl/6 mice. Three weeks from the paw injection of 3LL cells, Met-F-AEA reduced significantly the number of metastatic nodes, in a way antagonized by SR141716A. Our findings indicate that CB1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis.