Review
Cannabinoid pharmacology in cancer research: A new hope for cancer patients?
Introduction
It is known that cannabinoids, the active components of Cannabis sativa, act by mimicking the endogenous substances (the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG)) by activating specific cell-surface cannabinoid receptors (Devane et al., 1992). Currently, the cannabinoid receptor ligands are generally divided into three main categories known as phytocannabinoids, endogenous cannabinoids and synthetic cannabinoids (Fig. 1). After the clarification of the chemical structure of (-)-Δ9-tetrahydrocannabinol (Δ9-THC) which is the primary psychoactive component of the cannabis plant (Gaoni and Mechoulam, 1964a, Gaoni and Mechoulam, 1964b), other chemically related terpenophenolic compounds were identified in Cannabis sativa, including cannabichromene (CBC) (Gaoni and Mechoulam, 1966) and cannabigerol (CBG) (Gaoni and Mechoulam, 1964c). Although the pharmacology of most of the cannabinoids is unknown, Δ9-THC is the most widely studied owing to its high potency and abundance in cannabis (Pertwee et al., 2010). Among the herbal cannabinoids, other relevant plant-derived cannabinoids include Δ8-THC, which is almost as active as Δ9-THC but less abundant and cannabinol (CBN), which is produced in large amounts but is a weak cannabomimetic agent. Cannabidiol (CBD), CBG and CBC are devoid of psychoactive potential. The chemical structures of some cannabinoids are shown in Fig. 1.
So far, two cannabinoid-specific receptors CB1 and CB2 have been cloned and characterized from mammalian tissues (Howlett et al., 2002). Mouse CB1 receptor and CB2 receptor share 66% overall homology and 78% in the transmembrane region (Shire et al., 1996). Human CB1 receptor and CB2 receptor share an overall homology of 44%, and 68% in the transmembrane region respectively (Munro et al., 1993). Homology (96%) has been reported between human and mouse CB1 receptor (Chakrabarti et al., 1995), whilst human and mouse CB2 receptors share 82% homology (Shire et al., 1996). Many central and peripheral effects have been associated with the activation of CB1-receptors (Matsuda et al., 1990, Munro et al., 1993, Pertwee, 2006, Pertwee et al., 2010). The CB2 receptor, originally thought of as being exclusively present in the immune system, is highly expressed in B and T lymphocytes, macrophages and in tissues such as the spleen, tonsils and lymph nodes (Herkenham et al., 1991, Howlett et al., 2002, Porter and Felder, 2001, Pertwee et al., 2010). Recently CB2 receptors have been shown to be also located in the brain stem (Van Sickle et al., 2005). Further studies using CB1 knockout mice demonstrated that CB1 receptors are involved in a variety of different behavioural disorders such as depression, anxiety, feeding and cognition as well as pain at the peripheral, spinal and supraspinal levels (Valverde et al., 2005). Such studies using CB1 knockout mice also revealed the interactions between different systems such as opioids, gamma aminobutyric acid (GABA) and cholecystokinin (CCK) via CB1 receptors (Valverde et al., 2005). CB2 knockout mice have also been developed and revealed/confirmed the involvement of CB2 receptors in a variety of different systems such as immune system, inflammation, apoptosis, chemotaxis, bone loss, liver disorder, pain and atherosclerosis (Buckley, 2008).
Both CB1 and CB2 receptors are metabotropic and belong to the G-protein coupled receptor family (Howlett et al., 2002). Activation of CB1 and CB2 receptors stimulates cellular signalling via alpha subunit of G protein (Gi/o), leading to inhibition of adenylate cyclase and the subsequent activation of many other pathways such as mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways, modulation of ion channels (through CB1 receptors), protein kinase B (Akt), ceramide signalling pathways in tumour cells and modulation of cyclooxygenase-2 (COX-2) signalling pathway (Demuth and Molleman, 2006, Galve-Roperh et al., 2000, Glass and Northup, 1999, Guzman et al., 2001, Qamri et al., 2009).
There is also pharmacological evidence that non-CB1 and non-CB2 receptors mediate the actions of cannabinoids located in the brain (Breivogel et al., 2001, Di Marzo et al., 2000). The hypothesis that putative CB3 or non-CB1/CB2 receptor exist is supported by the fact that some of the anandamide (AEA)-mediated effects were neither inhibited by selective CB antagonists nor fully abolished in knockout mice lacking CB1 receptors (De Petrocellis and Di Marzo, 2010). Recent advances suggest, at least for AEA, that the transient receptor potential vanilloid 1 receptor (TRPV1) channel may be considered as the “third” receptor involved in endocannabinoid signalling (Di Marzo et al., 2001, Ross, 2003). For example, it has been shown that the endocannabinoids exert their apoptotic effect by binding to TRPV1, a non-selective cation channel targeted by capsaicin, the active component of hot chilli peppers (Smart and Jerman, 2000). However, the precise role of this receptor in cannabinoid signalling is still unclear and this uncertainty extends into the cancer field where its potential role in cancer biology (proliferation and migration of cancer cells) and cancer pharmacology (resistance to chemotherapeutic agents) needs further investigation (Lehen'kyi and Prevarskaya, 2011, Liberati et al., 2013). Evidence also exists supporting a role for peroxisome proliferator-activated receptors (PPARs) in the actions of cannabinoids (Sun and Bennett, 2007). More recent studies have provided evidence for the interaction of cannabinoids with the orphan receptors such as G protein receptor 55 (GPR55) (Andradas et al., 2011, Pineiro et al., 2011). Thus in addition to CB1 and CB2 receptors other targets might be involved in mediating an effect to cannabinoids and endocannabinoids.
The potential of cannabinoids to alleviate pain has been recognised for many centuries. The antinociceptive actions are mediated via both the CB1 and CB2 receptors (Pacher et al., 2006). This does not negate a role for other receptors such as TRPV1, transient receptor potential cation channel A1(TRPA1), orphan GPCR (i.e. GPR55) or PPAR-γ (Maione et al., 2006, Maione et al., 2013, Perez-Gomez et al., 2013, Moreno et al., 2014). For a long time, the development of cannabinoids as anticancer agents has been restricted to two therapeutic avenues (antiemetic and analgesic). They have therefore been evaluated in terms of palliative care as cannabinoids can play an important role in the relief of pain, nausea, vomiting, and stimulation of appetite in cancer patients. However, the involvement of CB receptors in pain and their use in the palliative care in cancer patients are not the focus of this review. In the present review, the aim is to focus on the anti-tumour effects of cannabinoids, identify potential mechanisms by which cannabinoids induce anti-tumour effects and discuss the potential and challenges for the future development of this class of compound.
Section snippets
Anti-tumour effects of cannabinoids
Whilst cannabinoids exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite, they have also been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. In 1975, Munson and collaborators were the first to report the anti-proliferative properties of cannabis compounds (Munson et al., 1975). They showed that Δ9-THC inhibits lung-adenocarcinoma cell growth in vitro and after oral
Cannabinoids and breast cancer
The first report on the antineoplastic property of cannabinoids in breast cancer are in the late 1990s, when it was shown that pre-treatment with the endocannabinoid anandamide inhibited prolactine- and nerve growth factor-induced proliferation of two hormone-sensitive, estrogen and progesterone (ER+/PR+) breast cancer cell lines (EFM-19 and MCF-7 cell lines). In this case, treatment reduced the levels of prolactin receptor (PRLr) and nerve growth factor receptors via CB1 receptor activation.
Cannabinoids and brain cancer
Both CB1 and CB2 receptors have been identified in the CNS (Ameri, 1999, Benito et al., 2007, Herkenham et al., 1991, Nunez et al., 2004, Skaper et al., 1996). High density of CB1 receptors has been reported in different areas of the brain such as in the cortex, cerebellum and hippocampus (Herkenham et al., 1991, Hoffman et al., 2010, Sullivan, 2000, Tsou et al., 1998). The CB1 receptor protein is mainly localised in astroglial cells and neurones whereas CB2 receptors are located on microglial
Cannabinoid and lung cancer
The first evidence of the antineoplastic activity of cannabinoids against lung cancer dates back to 1975 when Munson et al demonstrated a dose-dependent retardation in tumour growth in the Lewis lung adenocarcinoma animal model (Munson et al., 1975). Later on, further studies were carried out in order to elucidate the possible mechanism of action(s) of this class of molecule although controversial evidence about the anti-tumour action of cannabinoids were reported for this particular type of
Cannabinoids and intestinal cancer
Endocannabinoid signalling has been proved crucial for certain aspects of gastrointestinal homoeostasis. It also plays an essential role in the regulation of intestinal tumour growth. Recent studies have demonstrated an up-regulation of anandamide and its metabolite arachidonic acid in cancer tissues of patients with colon cancer with lymphatic metastasis (Chen et al., 2015). In addition, CB1 receptor expression was elevated (Chen et al., 2015). Another recent study also demonstrated that the
Cannabinoids and reproductive system cancer
During the last decade, increasing evidence has pointed towards the relevance of endocannabinoids in both female and male fertility. This association has been supported by the tightly modulated expression of cannabinoid receptor found in gonadal tissues. Along the male reproductive tract, CB receptors have been detected in the testis, Sertoli cells, prostate and vas deferens (Gye et al., 2005, Maccarrone et al., 2003, Pertwee et al., 2002, Rossato et al., 2005). CB receptors have also been
Conclusion and future direction
The substantial knowledge of palliative and anti-tumour actions of cannabinoids gained by the scientific community in the last few years has raised the profile of these molecules and many are promising candidates for cancer treatment. However, the use of cannabinoids in medicine is limited by their psychoactive effects, thus cannabinoid-based therapies that are devoid of unwanted side effects or with a safe profile/pharmacological window are required. A further aspect which complicates the
Conflict of interests/acknowledgement
FJ and AL disclose that they have received research support funding from GW Pharma.
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