Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast CarcinomaAlessia Ligresti, Aniello Schiano Moriello, Katarzyna Starowicz, Isabel Matias, Simona Pisanti, Luciano De Petrocellis, Chiara Laezza, Giuseppe Portella, Maurizio Bifulco and Vincenzo Di Marzo
JPET September 2006
Δ9-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 (IC50 between 6.0 and 10.6 μM), 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 CB2 and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca2+ 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 Δ9-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, CB1, and CB2 (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, 2005), two common side effects that accompany chemotherapy in cancer patients. Nevertheless, the use of cannabinoids in oncology might be somehow underestimated since increasing evidence exist that plant, synthetic, and endogenous cannabinoids (endocannabinoids) are able to exert a growth-inhibitory action on various cancer cell types. However, the precise pathways through which these molecules produce an antitumor effect has not been yet fully characterized, also because their mechanism of action appears to be dependent on the type of tumor cell under study. It has been reported that cannabinoids can act through different cellular mechanisms, e.g., by inducing apoptosis, cell-cycle arrest, or cell growth inhibition, but also by targeting angiogenesis and cell migration (for review, see Bifulco and Di Marzo, 2002; Guzman, 2003; Kogan, 2005). Furthermore, the antitumoral effects of plant, synthetic and endocannabinoids can be mediated by activation of either CB1 (Melck et al., 2000; Bifulco et al., 2001; Ligresti et al., 2003; Mimeault et al., 2003) or CB2 receptors or both (Sanchez et al., 2001; Casanova et al., 2003; McKallip et al., 2005), and, at least in the case of the endocannabinoid anandamide, by transient receptor potential vanilloid type-1 (TRPV1) receptors (Maccarrone et al., 2000; Jacobsson et al., 2001; Contassot et al., 2004) as well as by noncannabinoid, nonvanilloid receptors (Ruiz et al., 1999). Additionally, cannabidiol has been suggested to inhibit glioma cell growth in vitro and in vivo independently from cannabinoid and vanilloid receptors (Massi et al., 2004; Vaccani et al., 2005).
The main limitation of the possible future use of THC in oncology might be represented by adverse effects principally at the level of the central nervous system, consisting mostly of perceptual abnormalities, occasionally hallucinations, dysphoria, abnormal thinking, depersonalization, and somnolence (Walsh et al., 2003). However, most non-THC plant cannabinoids seem to be devoid of direct psychotropic proprieties. In particular, it has been ascertained that cannabidiol is nonpsychotropic (for review, see Mechoulam et al., 2002; Pertwee, 2004) and may even mitigate THC psychoactivity by blocking its conversion to the more psychoactive 11-hydroxy-THC (Bornheim and Grillo, 1998; Russo and Guy, 2006). Moreover, it has been recently found that systematic variations in its constituents (i.e., cannabidiol and cannabichromene) do not affect the behavioral or neurophysiological responses to marijuana (Ilan et al., 2005). Finally, it has been also shown that, unlike THC, systemic administration to rats of cannabigerol does not provoke poly-spike discharges in the cortical electroencephalogram during wakefulness and behavioral depression (Colasanti, 1990). These and other observations reinforce the concept that at least cannabidiol, cannabigerol, and cannabichromene lack psychotropic activity and indicate that for a promising medical profile in cancer therapy, research should focus on these compounds, which instead have been poorly studied with regard to their potential antitumor effects. By keeping this goal in mind, we decided to investigate the antitumor properties of cannabigerol and cannabichromene. We also screened THC acid and cannabidiol acid and two distinct Cannabis extracts (enriched in either cannabidiol or THC), where the presence of nonpsychotropic cannabinoids along with THC has been reported to mitigate the potential side effects of the latter compound in clinical trials (Russo and Guy, 2006).
Source with Charts, Graphs and Links: Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma