The current state and future perspectives of cannabinoids in cancer biology

Paweł Śledziński, Joanna Zeyland, Ryszard Słomski & Agnieszka Nowak

Cancer Medicine, 2018, 7, (3), 765–775.

doi : 10.1002/cam4.1312

 

Abstract

To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. In this review, we present an actual state of knowledge regarding molecular mechanisms of
cannabinoids’ anticancer action, but we discuss also aspects that are still not fully understood such as the role of the endocannabinoid system in a carcinogenesis, the impact of cannabinoids on the immune system in the context of cancer development, or the cases of a stimulation of cancer cells’ proliferation
by cannabinoids. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents.

 

Introduction

Nowadays, we observe an increasing public and scientific interest in the medical applications of Cannabis plants. In the USA, marijuana is now allowed for medical applications in 24 states and the District of Columbia. Hemp oil which has low concentration of Δ9-tetrahydrocannabinol is allowed in 16 subsequent states [1, 2]. Furthermore, during the last decade, we have collected a great pool of evidence from preclinical and clinical studies that Cannabis and cannabinoids have a therapeutic potential in many medical fields, and can even display some anticancer characteristics.

Cannabinoids

Cannabinoids are lipophilic ligands for specific cell-surface cannabinoid receptors (CB). This class of molecules can be divided into three main groups: phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Phytocannabinoids are secondary metabolites of Cannabis plants. About 100 phyto-cannabinoids have been described, of which Δ9-tetrahydrocannabinol (THC) is main psychoactive compound. Action of THC in human organism relies on mimicking endogenous agonists of CB receptors—endocannabinoids [3]. It is responsible for euphoria and has analgesic, antiemetic, and anti-inflammatory properties, however, its psychoactivity strongly limits medical potential [4]. Another phytocannabinoid which gains medical attention is cannabidiol (CBD). It has low affinity for cannabinoid receptors and acts independently of them. CBD interacts with other receptors such as transient receptor potential channel subfamily V member 1 (TRPV1), orphan G-protein coupled receptor (GPR55), or peroxisome proliferator-activated receptors (PPARs). They have been proposed to be classified as CB receptors, but their exact role in endocannabinoid signaling is still under discussion [3]. CBD has anxiolytic properties and attenuates THC psychoactive effects [4]. Endocannabinoids are part of the endocannabinoid system, which is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in their metabolism. The most widely studied endocannabinoids are anandamide (AEA) and arachidonoylglycerol (2-AG).

To date, two cannabinoid receptors (CB1 and CB2) have been identified in mammalian tissues [5, 6]. They belong to G-protein coupled receptor family [3]. The activation of each of them leads to an inhibition of adenylyl cyclase via G proteins (Gi/o), which in turn activates many metabolic pathways such as mitogen-activated protein kinase pathway (MAPK), phosphoinositide 3-kinase pathway (PI3K), cyclooxygenase-2 pathway (COX-2), accumulation of ceramide, modulation of protein kinase B (Akt), and ion channels [3, 7]. Most of the cannabinoids’ effects in neural and nonneural tissues rely on activation of CB1 receptor. Its high expression has been observed in these areas of central nervous system, that are engaged in the modulation of motor behavior, memory, learning, emotions, perception, and endocrine functions [3, 8]. Studies using CB1 knockout mice suggest that this receptor plays a role also in behavioral disorders such as depression, anxiety, feeding, or cognition [9]. CB2 receptors have been found in immune cells, but their presence was revealed also in nervous system [10, 11]. In addition to its neuromodulatory function, endocannabinoid system has been shown to play other important functions such as control of the energy metabolism, immunity, cardiovascular tone, and reproduction [12, 13].

According to the contribution of the endocannabinoid system in a regulation of such variety of processes, its pharmacological modulation becomes promising therapeutic strategy. To date, cannabinoids have been exploited in the palliative medicine. In the USA there are two cannabinoid-based drugs approved for use by US FDA: nabilone and dronabinol. Nabilone (THC synthetic analogue) is allowed for the treatment of nausea and vomiting induced by chemotherapy, and sleep disorders. Dronabinol (synthetic THC) is approved also for nausea and vomiting due to chemotherapy and for the treatment of weight loss associated with AIDS. Another drug approved outside the USA (Austria, Canada, Czech Republic, Demark, France, Germany, Italy, Poland, Spain, Sweden, United Kingdom) is nabiximols (Sativex®, oromucosal spray, THC and CBD in 1:101 ratio), which is allowed for a treatment of spasticity associated with multiple sclerosis. Medical Cannabis in the form of marijuana (dried flowers and leafs) is illegal in the USA at the federal level according to the Controlled Substances Act 1970 as a Schedule I substance, but some states have legalized it for medical purposes [14].

Besides palliative properties of cannabinoids, it has been shown in wide range of in vitro and animal models, that they also exhibit anticancer effects [7, 15–17].

Endocannabinoid system and cancer

Despite numerous studies conducted during the last decade, there are still inconsistent data regarding the exact role of cannabinoid system in cancer development. The upregulated expression of CB receptors and the elevated levels of endocannabinoids have been observed in a variety of cancer cells (skin, prostate, and colon cancer, hepatocellular carcinoma, endometrial sarcoma, glioblastoma multiforme, meningioma and pituitary adenoma, Hodgkin lymphoma, chemically induced hepatocarcinoma, mantel cell lymphoma), but it is not always correlated with the expression level of these receptors in tissue of origin [7, 11, 18, 19]. Furthermore, concentration of endocannabinoids, expression level of their receptors, and the enzymes involved in their metabolism frequently are associated with an aggressiveness of cancer. This implies that an overactivation of endocannabinoid system might be protumorigenic and plays an essential role in the development of cancer [20, 21]. It has been shown that absence of CB receptors leads to decrease in ultraviolet-light skin carcinogenesis in murine model [22]. In agreement with this, CB2 receptor contributes to human epidermal growth factor receptor (HER2) pro-oncogenic signaling and an overexpression of CB2 increases susceptibility for leukemia development after leukemia viral infection [23, 24].

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