Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol

Abstract

Purpose

Colon cancer is a major public health problem. Cannabis-based medicines are useful adjunctive treatments in cancer patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS, i.e. CBD botanical drug substance, on colorectal cancer cell proliferation and in experimental models of colon cancer in vivo.

Methods

Proliferation was evaluated in colorectal carcinoma (DLD-1 and HCT116) as well as in healthy colonic cells using the MTT assay. CBD BDS binding was evaluated by its ability to displace [³H]CP55940 from human cannabinoid CB₁ and CB₂ receptors. In vivo, the effect of CBD BDS was examined on the preneoplastic lesions (aberrant crypt foci), polyps and tumours induced by the carcinogenic agent azoxymethane (AOM) as well as in a xenograft model of colon cancer in mice.

Results

CBD BDS and CBD reduced cell proliferation in tumoral, but not in healthy, cells. The effect of CBD BDS was counteracted by selective CB₁ and CB₂ receptor antagonists. Pure CBD reduced cell proliferation in a CB₁-sensitive antagonist manner only. In binding assays, CBD BDS showed greater affinity than pure CBD for both CB₁ and CB₂ receptors, with pure CBD having very little affinity. In vivo, CBD BDS reduced AOM-induced preneoplastic lesions and polyps as well as tumour growth in the xenograft model of colon cancer.

Conclusions

CBD BDS attenuates colon carcinogenesis and inhibits colorectal cancer cell proliferation via CB₁ and CB₂ receptor activation. The results may have some clinical relevance for the use of Cannabis-based medicines in cancer patients.

Introduction

Cancer is a prominent health problem in the world. One in 4 deaths in the United States is due to cancer (Siegel et al. 2013). Colorectal cancer represents the third most common cancer worldwide, both in men and women, with 142,820 new cases and 50,830 deaths estimated to occur in 2013 (Siegel et al. 2013). Pharmacoeconomic studies have highlighted a trend for rising costs associated with colorectal cancer, which is linked to the increasing use of targeted biological therapies (Kriza et al. 2013). Screening strategies are utilized but have not reduced disease incidence or mortality (Derry et al. 2013). Furthermore, therapeutic intervention, which is by itself very toxic, may fail to prevent disease progression to metastatic disease (Ebos and Kerbel 2011). Therefore, there is an interest in both cancer preventive strategies – which include experimentation with safe phytochemical agents – and new curative treatments (Franceschi and Wild 2013).

Cannabis extracts and plant-derived cannabinoids (named phytocannabinoids) have demonstrated direct anti-cancer effects and are also used in cancer patients to stimulate appetite and as antiemetics (Fowler et al., 2010, Carter et al., 2011, Pertwee, 2012, Velasco et al., 2012, Massi et al., 2013). Recent progress in plant biotechnology has made possible the cultivation of Cannabis chemotypes rich in specific phytocannabinoids, from which standardized extracts, containing known amounts of phytocannabinoids, may be obtained (Russo 2011). The best studied among these extracts is generally referred as cannabidiol (CBD) botanical drug substance (CBD BDS, that is a standardized Cannabis extract with high content of CBD). In several pharmacological assays, CBD BDS has been shown to be more potent or efficacious than pure CBD (Comelli et al., 2008, Capasso et al., 2011, De Petrocellis et al., 2013, Russo, 2011), suggesting additive or synergistic interactions can occur between CBD and minor phytocannabinoids (or the non-cannabinoid fraction) contained in the extract, which, in turn might be useful from a therapeutic viewpoint. CBD is the most common phytocannabinoid in fibre (hemp) plants, it is non-psychotropic and, among potent and different pharmacological actions, it exerts antitumoural actions both in vitro and in vivo (Ligresti et al., 2006, Wilkinson and Williamson, 2007, Sreevalsan et al., 2011, McAllister et al., 2011, Maor et al., 2012, Ramer et al., 2012, Solinas et al., 2012, Hernán Pérez de la Ossa et al., 2013). Of relevance to the present investigation, is our recent discovery that CBD exerts antiproliferative effects in colorectal carcinoma cells and chemopreventive actions in an experimental model of colon cancer (Aviello et al. 2012).

Therefore, here we extended our previous investigations of the intestinal antitumoural action of CBD (Aviello et al. 2012) by exploring the effect and the mode of action of CBD BDS in colorectal carcinoma cells and in in vivo murine models of colon carcinogenesis.