Review Article Clinical and Medical Investigations Clin Med Invest, 2017 doi: 10.15761/CMI.1000147 Volume 2(4): 1-5 ISSN: 2398-5763 Novel therapeutic applications of cannabinoids in cancer disease Walter Milano 1 , Mario F Tecce 1 and Anna Capasso 2 * 1 Mental Health Unit District 24 ASL Napoli 1 Center, Italy 2 Department of Pharmacy, University of Salerno, 84084-Fisciano, Italy Abstract Te endocannabinoid system, comprising the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids), and the proteins that regulate endocannabinoid biosynthesis and degradation, controls several physiological and pathological functions. Indeed, recent evidence indicates that endocannabinoids infuence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to both in vitro and in vivo antitumour efects. Also, the endogenous ligand arachidonoyl ethanolamide (anandamide; AEA) inhibits the proliferation of human breast cancer cells by blocking the G0/G1-S-phase transition of the cell cycle through interference with cannabinoid CB1 receptor-coupled signal-transducing events. Te present review shows that cannabinoids exert their anti-cancer efects in a number of ways and in a variety of tissues. Furthermore, the novel therapeutic applications of cannabinoids in cancer disease, described here, strongly support the idea that cannabinoids may induce benefcal efect in cancer treatment. Correspondence to: Anna Capasso, Department of Pharmacy, University of Salerno, 84084-Fisciano, Italy, E-mail: annacap@unisa.it Key words: cannabinoid, cancer treatment, therapeutic application Received: November 10, 2017; Accepted: December 12, 2017; Published: December 16, 2017 Introduction Te recreational use of Cannabis Sativa preparations is known to most people, largely as a result of the explosion in its use in the late 1960s; indeed, marijuana is still one of the most widespread illicit drugs of abuse in the world [1]. However, the medicinal use of Cannabis also has a millenarian history [2], although this history has been re- examined only very recently [3]. As early as 2600 BC, the Chinese emperor Huang Ti advised taking Cannabis for the relief of cramps, and rheumatic and menstrual pain; however, the great therapeutic potential of Cannabis was not scientifcally assessed and publicized in the Western world until the British physician O’Shaugnessy wrote on the topic in the nineteenth century [2]. Tis long history of Cannabis use has resulted in the development of pharmaceutical drugs, such as dronabinol (Marinol;Unimed). Tis preparation, prescribed in the United States as an anti-emetic and appetite-stimulants to patients with cancer and AIDS, is based on Δ 9 -tetrahydrocannabinol (THC), which in 1964 by Mechoulam and coworkers was identifed as the major psychoactive component of cannabis. To date, some 60 plant terpenophenols more or less related to THC have been isolated and defned cannabinoids [4]. Although the pharmacology of most of the cannabinoids is unknown, it is widely accepted that Δ 9 -tetrahydrocannabinol is the most important, owing to its high potency and abundance in cannabis. Cannabinoid receptors So far, two cannabinoid-specifc receptors have been cloned and characterized from mammalian tissues, the seven transmembrane G protein-coupled cannabinoid receptors type 1 (CB1 receptor), [5] and type 2 (CB2 receptor) [6]. Both the central efects and many of the peripheral efects of cannabinoids depend on CB1 receptor activation. Expression of this receptor is abundant in the brain, particularly in the basal ganglia, cerebellum and hippocampus, which accounts for the well-known efects of cannabis on motor coordination and short term memory processing [7]. Te CB1 receptor is also expressed in peripheral nerve terminals and various extraneuronal sites such as the testis, eye, vascular endothelial and spleen. By contrast, the CB2 receptor is almost exclusively expressed in the immune system, both by cells, including B and T lymphocytes and macrophages, and by tissues, including the spleen, tonsils and lymph nodes [8-10]. Pharmacological evidence exists for the presence of other cannabinoid receptors, which, however, have not yet been cloned [11]. CB1 and CB2 receptors share only 44% overall identity and 68% within the transmembrane domains. Both cannabinoid receptors cloned so far are coupled to G proteins, mostly of the G i/o type, through whose α subunit they modulate the activity of adenylate cyclases (inhibited) and mitogen-activated protein kinases (stimulated). CB1 receptors are also coupled to modulation of voltage-activated Ca 2+ channels (inhibited) and inwardly rectifying K + channels (stimulated), and activation of both phospholipase C (via the βγ subunits of the G protein) and PI-3-kinase. CB2 receptors, on the other hand, trigger a sustained activation of ceramide biosynthesis [12]. Cannabinoids and cancer Te ubiquity of the endogenous ligands of cannabinoid receptors in both vertebrate and invertebrate tissues, and their modulating activity on proteins and nuclear factors involved in cell proliferation, diferentiation and apoptosis, suggest that the endocannabinoid signalling system is involved, among other efects, in the control of cell survival transformation and proliferation. Te anti-proliferative properties of cannabis compounds were frst reported almost 30 years ago by Munson et al., who showed that THC inhibits lung-