Cannabinoids, Endocannabinoids and Cancer
Daniel J. Hermanson and Lawrence J. Marnett
Cancer Metastasis Reviews, 2011, 30, (3-4), 599–612.
1.1 Cannabinoid Function
Endocannabinoids are bioactive lipids that have a range of interesting activities mediated by two G-protein-coupled receptors (CB1 and CB2) and other putative targets [1-3]. The CB1 receptor is present in the central nervous system and mediates the psychotropic effects of exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC), the active component of marijuana. In the brain, endocannabinoids and cannabinoids combine with CB1 cannabinoid receptors on axon terminals and regulate ion channel activity and neurotransmitter release . Binding to the CB1 receptor is responsible for the analgesic activity of endocannabinoids as well as many other effects including locomotion and temperature
control . The CB2 receptor is present in inflammatory tissues and mediates the antiinflammatory effects of endocannabinoids and plant-derived cannabinols . Both the CB1 and CB2 receptors couple to Gi and reduce intracellular cAMP levels.
1.2 Biosynthesis and Degradation of Endocannabinoids
Endocannabinoids are synthesized “on demand” by post-synaptic cells and function as retrograde signaling molecules, diffusing back across the synapse to bind with pre-synaptic CB1 receptors, which reduces synaptic transmitter release . The endocannabinoids are primarily produced biosynthetically from phospholipids . The two primary endocannabinoids are anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG). The most frequent biosynthetic route for AEA is through the transfer of arachidonic acid (AA) from the sn-1 position of phosphatidylcholine (PC) to the nitrogen atom ofphosphatidyl-ethanolamine (PE) by N-acyl transferase (NAT) to form N-arachidonoyl-phosphatidyl-ethanolamine (NAPE) [8, 9]. NAPE is then converted into AEA in a one-step hydrolysis reaction catalyzed by the NAPE-specific phospholipase D (NAPE-PLD) (Figure 1) . 2-AG is most frequently synthesized through the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) with AA on the sn-2 position to diacylglycerol (DAG) by phospholipase C-β (PLC-β). The DAG is then hydrolyzed to 2-AG by diacylglycerol lipase (DAGL) (Figure 2) [7, 11, 12].
The inactivation of endocannabinoids occurs by enzyme-catalyzed hydrolysis to AA; 2-AG is hydrolyzed by monoacylglycerol lipase (MAGL) and AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) (Figure 3) [13, 14]. Endocannabinoids are also substrates for cycloxygenase-2 (COX-2), lipoxygenases (LOXs), and cytochromes P450 (CYP450s) and it is possible that these enzymes also play a role in controlling endocannabinoid levels by oxygenating 2-AG and AEA . Induction of COX-2, LOXs, and CYP450s at sites of inflammation or in tumor cells could reduce the levels of naturally occurring antiinflammatory and anti-proliferative lipid mediators. Furthermore, the products of endocannabinoid metabolism may exert effects that stimulate inflammation or tumor cell development by activating receptors that are distinct from classic receptors or by hydrolysis to products that are known to contribute to both inflammation and tumorigenesis 
Although the original focus of endocannabinoid biology was on neurological and psychiatric effects, these molecules are increasingly appreciated for their role in inflammation and cancer. The role of endocannabinoids in cancer has been implied by studies of the effects of exogenous cannabinoids, many derived from the plant Cannabis sativa, and synthetic compounds with activity at the CB1 and CB2 receptors (Figure 4). Endocannabinoids inhibit proliferation of cancer cells in culture and in vivo [17, 18]. In addition, endocannabinoids inhibit colonic inflammation, and deletion of CB receptors enhances colonic inflammation and cancer [19-21].
2. Cannabinoids and Cancer
2.1 Cannabinoid and Endocannabinoid Mediated Effects
Many laboratories have proposed that cannabinoids and endocannabinoids directly inhibit tumor growth in vitro and in animal tumor models through several different pathways. The inhibition of tumor growth and progression of several types of cancers including glioma, glioblastoma, breast cancer, prostate cancer, thyroid cancer, colon carcinoma, leukemia, and lymphoid tumors have been demonstrated by natural and synthetic cannabinoids, endocannabinoids, endocannabinoid analogs, endocannabinoid transport inhibitors, and endocannabinoid degradation inhibitors. Several different mechanisms have been implicated in the anti-tumorigenic actions of endocannabinoids and include cytotoxic or cytostatic effects, apoptosis induction, and anti-metastatic effects such as inhibition of neoangiogenesis and tumor cell migration . These effects are dependent on CB1, CB2,
transient receptor potential vanilloid type 1 (TRPV1), or are receptor-independent based on the cannabinoid or endocannabinoid and the tissue or tumor cell.
Endocannabinoid levels are finely modulated under physiological and pathological conditions. A transient increment appears to be an adaptive reaction to restore homeostasis when this is acutely and pathologically perturbed. However, in some chronic conditions, the alteration of the endocannabinoid system seems to contribute to the progress and symptoms of the disease. In particular, several different types of cancer have abnormally regulated endocannabinoid systems.
2.2 Changes in Endocannabinoid Tone and Signaling in Tumors
Elevated levels of AEA and 2-AG have been reported in several types of tumors when compared with their normal counterparts, specifically in glioblastoma, meningioma, pituitary adenoma, prostate and colon carcinoma, endometrial sarcoma, and in highly invasive human tumor cells [22-27]. The enzymes that synthesize and metabolize the endocannabinoids control their effects by modulating the localized concentrations. A correlation between endocannabinoid metabolizing enzymes, FAAH (for AEA) and MAGL (for 2-AG), and cancer has been investigated in prostate adenocarcinomas. MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and pharmacological or RNA-interference disruption of MAGL impairs prostate cancer aggressiveness . An increase of FAAH expression in prostate cancer compared to normal prostate tissue samples has been reported . In contrast, in human patients with pancreatic ductal adenocarcinomas a correlation between high FAAH and MAGL levels and survival has been observed .