Encyclopedia
Please note this is a comparison between Version 1 by Igor Kovalchuk and Version 2 by Vivi Li.
CThe endocannancer is a disease which affects approximately 40% of people in their lifetime. Chemotherapy, the primary choice for treatment of cancer, is often ineffective or/and presents itself with many debilitating side effects, including loss of appetite, nausea, insomnia, and anxiety. Cbinoid system (ECS) is an ancient homeostasis mechanism operating from embryonic stages to adulthood. It controls the growth and development of many cells and cell lineages. Dysregulation of the components of cannabis extracts, including cannabinoids and terpenes, may present an alternative for the ECS may result in uncontrolling side effects and may be used for tumor shrinkage together with chemodrugs. Cannabinoids act on so called endocannabinoid system (ECS) that operates in human body to maintain homeostasis. ECS promotes healthyed proliferation, adhesion, invasion, inhibition of apoptosis and increased vascularization, leading to the development of tissues and regulates many processes in our organism and when disbalanced may lead to disease, including cancervarious malignancies. Cancer is the disease of uncontrolled cell division.
- endocannabinoid system
- cancer and carcinogenesis
- primary care
- palliative care
- cannabinol
- tetrahydrocannabinol
1. Introduction
Endocannabinoid system (ECS) is an ancient (over 600 mln years old), evolutionary stable animal homeostasis system [1]. It consists of three components—ligands, including 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA or anandamide), receptors, such as cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and the metabolizing enzymes—fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). As a regulator of homeostasis, ECS regulates the activity of brain, endocrine, and immune systems, among others. One such regulatory mechanism is the regulation of energy metabolism. ECS increases the energy intake, facilitates its storage, and decreases the expenditure [2]. Central regulators of energy metabolism, such as hypothalamic orexigenic neuropeptide Y (NPY) and anorexigenic cocaine and amphetamine regulated transcript (CART) peptide and peripheral regulators, such as leptin (LEP), ghrelin (GHRL) adiponectin (ADIPOQ), and cholecystokinin (CCK), are known to be dysregulated in various cancers and to contribute to malignancy (reviewed in [3]).
Genes responsible for energy homeostasis play essential roles in the organism, and dysregulation of energetic metabolism not only results in the development of metabolic syndrome, obesity, and diabetes, but is also linked to many cancers [4]. Detailed description of the role of ECS in controlling energy homeostasis is beyond the scope of this rentryview and is presented well elsewhere [5].
Cancer is a disease of dysregulated and uncontrolled cell division and cell proliferation. Successful malignization requires mutations in multiple genes [6]. Numerous theories of cancer development and progression exist. Currently, most cancers have no cure; even so, significant progress in the development of chemotherapy and immune therapy of cancers has been achieved. Cancer therapy consists of primary care, directed at tumor eradication and palliative care, which aims to reduce side effects and suffering of a patient.
Cannabinoids as endogenous regulators of homeostasis are the molecules that can potentially be used for cancer therapy. They may be particularly useful in palliative care.
2. Role of Endocannabinoids in the Human Body
ECS is active in virtually all cells of houmanr organism. It plays an important role in the reproduction, function, and proper development of gametes [7], fertilization event, embryo implantation, and proper placenta development [8]. It is also active at all stages of embryogenesis, regulating cell division, and tissue and organ development, specifically, regulating differentiation of neural progenitors, synaptogenesis, and axonal migration [9]. During human adult life, it regulates homeostasis of many tissues, playing critical role in proper brain function by regulating neuronal synaptic communications affecting critical organismal functions, including general metabolism, growth and development, reproduction, learning and memory formation, mood, and behavior, among others [10]. In the peripheral tissues, endocannabinoids are involved in endocrine regulation and energy balance [11], as well as regulating the function of innate and adaptive immune system and immune response [12], regulating cell migration and apoptosis. The activity and functionality of ECS depends on many factors, from cell- and tissue-specific differences in the synthesis of endocannabinoids, to the number and the activity of endocannabinoid and auxiliary receptors, to the expression and the activity of enzymes involved in the degradation of circulating endocannabinoids. In the cells, endocannabinoids acting in CB-receptor-dependent and independent manner exhibit anti-oxidative properties, are involved in clearance of damaged molecules and regulate mitochondrial activity. Anti-oxidative properties are associated with the inhibition of production of reactive oxygen species (ROS), metal chelation and prevention/alleviation of ROS-induced cell damage [13]. It should be noted that the anti-oxidative effects of cannabinoids are cell specific—while in most cells of the body, they mitigate oxidative stress, in hepatic cells they may cause it, leading to cell death [14]. Similarly, in cancer cells, such as gliomas and leukemia, cannabinoids promote oxidative stress [13]. Cannabinoids contribute to recycling of damaged molecules and are likely involved in autophagy in health tissues [15]—the activity well documented in cancer cells (discussed below). In normal cells, they increase lysosomal stability and integrity [15] through CB1 receptors found on the surface of lysosomes. CB1 receptors are also present on the surface of mitochondria. They regulate mitochondrial oxidative phosphorylation in a positive and a negative manner, acting through the CB1 receptor, but it is not clear what modulates this activity [13]. When cells are stressed, cannabinoids attenuate mitochondrial damage [16] and decrease calcium-induced cytochrome c release [17].2.1. Mechanism of Action—Ligand/Receptor
Cannabinoid receptors are ubiquitous and expressed on the cell surface as well on cell organelles, including mitochondria and lysosomes. Classical cannabinoid receptors include CB1 and CB2. CB1 is expressed at a higher level in central and peripheral nervous systems, while CB2 is expressed in many different tissues, including the immune system, internal organs, skin, bone, muscle, and glia in the brain [18]. CB1 and CB2 are GPCR (Gi/o) protein-coupled receptors, and when activated, they modulate various cellular functions through receptor internalization; interaction with other G-protein-coupled receptors; inhibition of adenylyl cyclase activity, changing the activity of calcium and potassium channels; increasing phosphorylation of various mitogen-activated protein kinases (MAPK); and many more functions [12] (Figure 1).
Figure 1. Biosynthesis, degradation, and interaction of endocannabinoids with cannabinoid receptors. Biosynthesis and the inactivation of the two endogenous lipid messengers, such as endocannabinoids N-Arachidonoylethanolamine or anandamide (AEA), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamide (PEA) act on cannabinoid receptors. AEA and 2-AG are typically released on demand from membrane lipids. AEA synthesized from N-arachidonoyl-phosphatidylethanolamines (NAPE) via the activity of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and hydrolyzed by fatty acid amide hydrolase (FAAH) to ethanolamine and arachidonic acid (AA). 2-AG is 2-AG can also be produced from sn-2-arachidonate-containing diacylglycerols by sn-1-acyl-2-arachidonoylglycerol lipase (DAGL), and degraded by lipase (MAGL), releasing glycerol and AA. PEA is hydrolyzed by N-acylethanolamine-hydrolyzing acid amidase (NAAA) into ethanolamine and palmitic acid (PA). Cyclooxygenase-2 (COX-2) can also oxidize anandamide and 2-AG, followed by prostaglandin synthases to produce prostamides (from anandamide) and prostaglandin-ethanolamide, PG-EA (from 2-AG). Both AEA and 2-AG move across the plasma membrane via a purported endocannabinoid membrane transporter (EMT) and target CB1 and CB2, which show an extracellular binding site. 2-AG, AEA, and PEA directly activate orphan G-protein-coupled receptors (GPR55, GPR18, GPR119), the transient receptor potential of vanilloid (TRPV) channel, and peroxisome proliferator-activated nuclear receptors (PPARs). Dashed lines denote low-affinity bindings. Phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and Δ9-tetrahydrocannabivarin (THCV) showed to activate cannabinoid receptors. CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; ER, endoplasmic reticulum. This figure was created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com (accessed on 4 May 2022)).
2.2. Role in the Control of Cell Division and Cell Proliferation
It appears that ECS controls the fate of many cells in the organism, regulating the cell division and proliferation, apoptosis, necrosis and autophagy in several organs and organ systems, including the brain, skin, and immune system. In the central nervous system (CNS), the ECS system functions as a neuroprotective system that controls glutamate excitotoxicity, calcium influx, inflammation, and autophagy [25]. In the CNS, the interaction of endocannabinoids with CB1/CB2 and other receptors mediates synaptic plasticity or progenitor cell fate in the central nervous system, promoting self-repair of the brain [26]. It also appears that constitutive release of 2-arachidonoylglycero by late oligodendrocyte progenitors allows oligodendrocyte maturation by activating CB receptors and downstream ERK pathway [27]. In skin, ECS activity maintains the cutaneous homeostasis through the regulation of skin cell proliferation, survival, and differentiation [28]. Locally produced AEA inhibits the cellular growth and the differentiation of cultured NHEK and HaCaT keratinocytes, as well as inducing apoptosis of human HaCaT keratinocytes [28]. CB1 activity is higher in differentiated skin layers [29]. In human cultured hair follicles, AEA but not 2-AG inhibit elongation and proliferation of hair shaft and induce intraepithelial apoptosis in a CB1-dependent manner [30]. Both AEA and 2-AG induce apoptosis of human sebaceous-gland-derived SZ95 sebocytes in a CB2-dependent manner [31]. In the immune system, the central role is played by CB2 receptors that are mainly expressed by cells (T and B lymphocytes) and peripheral tissues of the immune system (spleen and thymus) where it regulates immune suppression, apoptosis, and cell migration [32]. In in vitro studies, it was demonstrated that anandamide inhibits mitogen-induced proliferation of T cells [33], while inhibiting the chemokine SDF-1-induced migration of CD8+ T cells [34]. In contrast, 2-AG, but not anandamide, induced CB2-dependent migration in natural killer cell line KHYG-1 cells [35]. In B cells, 2-AG chemo-attracts naïve B cells and marginal zone B cells and inhibits the function of activated B cells, while 2-AG and anandamide suppress the migration of neutrophils [36]. Additionally, anandamide induces the apoptosis of murine bone-marrow-derived DCs (BMDCs) in a CB1- and CB2-dependent manner [37].2.3. Changes in the ECS with Age
Cancer can be considered an age-associated disease, due to the accumulation of cellular and DNA damage. From this perspective, it is interesting to understand what happens to ECS with age. In general, information about age-related changes in the ECS is scarce. Most of the data are related to changes in the central nervous system, and even then, the data are very contradictory. In general, it is believed that the activity of ECS declines with age [13]. In rats, in one study, a general decrease in the expression of CB1 and a decrease in density of the receptors in various brain areas with age was observed [38], while in another study—in which only redistribution of the receptors was noted– they were reduced in the postrhinal, but elevated in the entorhinal and temporal cortices in old animals [39] (Table 1). In mice, no changes in the receptor density in most brain regions was found with age, but instead, a significantly reduced receptor/Gi protein coupling was observed [40]. In one study on humans, CB1 expression increased, predominantly in females, most drastically in the basal ganglia, the lateral temporal cortex, and in the hippocampus [41], while another study reported no change [39]. As for endocannabinoids, the picture is not clear either—some studies suggested a decrease, while others found no difference in different brain regions of young and old animals. [13]. However, animals lacking FAAH—the enzyme degrading anandamide showed less pronounced features of aging—decreased expression of pro-inflammatory genes and decreased decline in cardiac function [42] (Table 1).Table 1.
Age-dependent changes to ECS components in different normal tissues.
| Tissues/Organs | Endocannabinoids | Receptors | Metabolizing Enzymes |
|---|---|---|---|
| Skin | No reliable data | ↓ in CB1 expression [13] | FAAH tends to ↓ with age [43][45] |
| Lung | 2-AG ↓ and AEA ↑ in mice [44][46] | No reliable data | No reliable data |
| Brain | From no change [40] to a ↓ in AEA [45][47] ↓ in 2-AG levels in mice [46][48] |
From ↑ in humans [41] to no change [39] to a ↓ [38][47][38,49] in mice/rats in CB1 expression, brain area-specific | ↓ FAAH activity in rats [48][50] ↑ in MAGL levels in mice [46][48] |
| Blood | Small ↑ in 2-AG and AEA in mice [44][46] | No reliable data | No reliable data |
↑ Indicates increased expression or the amount of circulating product, while ↓ indicates decreased amounts.
Very little reliable data exist on changes in the ECS in skin. Concentration of AEA is 119-fold higher than 2-AG in human skin [49][43], although it is not known how it changes with age. Moderate CB1 activation in skin works as a suppressor of the differentiation, while high activation leads to anti-proliferative and pro-apoptotic events [19]. In mice, CB1 deficiency in skin may lead to premature aging [50][44]. CB1-deficient mice exhibit cognitive impairments and changes in the structure of skin, indicating that CB1 deficiency accelerates aging only in the brain and in the skin, but not other peripheral organs [50][44].
Expression of anandamide degrading enzyme FAAH decreases with age and in response to sunburn in skin [43][45], indicating that ECS may undergo similar changes upon skin aging and in response to UV damage. A decrease in FAAH with age may also mean that there is less anandamide produced with age.
There is even less information about ECS activity in other tissues. One report shows a 2-AG decrease in lungs and increase in blood, while AEA increases in lung and blood in mice [44][46].
3. Effect of Cannabinoids on Various Hallmarks of Cancer
Various in vitro and in vivo experiments have shown that cannabinoids can target almost every hallmark of cancer (Figure 2) [51][186]. They inhibit proliferation, reduce inflammation, stimulate apoptosis, and inhibit tumor invasiveness, angiogenesis, and metastasis [52][53][54][55][187,188,189,190]. One of the most important effects of cannabinoids, besides their antitumor ability, is that they are less likely to affect non-transformed normal cells surrounding tumors, and they may even have protective effects. For instance, cannabinoids may induce cell death in glioma cells while protecting normal astroglial and oligodendroglial cells from apoptosis via CB1 receptors [52][187]. Studies on animals show the protective effects of cannabinoids against certain types of tumors. For example, a dose-dependent decrease in the incidence of hepatic adenomas and hepatocellular carcinomas in mice that were given THC over 2 years was noted. Additionally, lower incidence rates of benign tumors in mammary glands, uterus, testis, and pancreas were seen in tested rats [56][191].Figure 2. The effects of cannabinoids on different hallmarks of cancer. The activation of cannabinoid 1 (CB1), cannabinoid 2 (CB2), and transient receptor potential cation channel 1 (TRPV1) increase levels of anandamide (AEA), as well as inhibition of G-protein coupled receptor 55 (GPR55), and exert different effects on tumor cells in respect to cancer hallmarks. Cannabinoids inhibit tumor-promoting inflammation via downregulation of nuclear factor κB (NFκB), signal transducer and activator of transcription 5 (STAT5), and interleukin 1 (IL1). The angiogenesis is inhibited by reduction in vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1α (HIF1α). Next, invasion and metastasis are prevented by decrease of tissue degrading enzymes—matrix metalloproteinase 2 and 9 (MMP2, MMP9), as well as expression of intercellular adhesion molecule 1 (ICAM-1). Sustained proliferative signaling is opposed by the activation of p21 and p27 that leads to cell cycle arrest. Lastly, under the action of cannabinoids, cell death may be achieved by three mechanisms. Autophagy is triggered by inhibition of protein kinase B (AKT), phosphoinositide 3-kinase (PI3K) and mammalian inhibitor of rapamycin (mTOR). Apoptotic cell death is a result of upregulation of pro-apoptotic and downregulation of anti-apoptotic factors under the action of different cannabinoids. Necrosis can result due to high Ca2+ release and formation of ROS in cancer cells. This figure was created with BioRender.com.
