Tag Archives: Cannabinoids
Cannabinoid Receptors, CB1 and CB2, as Novel Targets for Inhibition of Non-Small Cell Lung Cancer Growth and Metastasis
“Cannabinoid receptors are expressed in human lung cancers”
“Recently, CB1 and CB2 have been shown to be overexpressed on tumor cells compared to normal cells in various types of cancers, such as breast and liver, and therefore could be used as novel targets for cancer. In addition, several cannabinoids, including THC and cannabidiol, synthetic cannabinoid-agonists JWH-133, Win55,212-2, were shown to inhibit tumor growth and progression of several types of cancers, including glioma, glioblastoma multiforme, breast, prostate, colon carcinomas, leukemia and lymphoid tumors.”
“There are three general types of cannabinoids: phytocannabinoids, THC and cannabidiol, are derived from plants; endogenous cannabinoids, 2AG and AEA, which are produced inside the body; and synthetic cannabinoids, JWH-133/JWH-015, CP-55 and Win55,212-2.”
“Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC…”
“These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025486/
Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1.
“Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion.”
“Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.”
“There is considerable evidence to suggest an important role for cannabinoids in conferring anticarcinogenic activities. In this study, we identified TIMP-1 as a mediator of the anti-invasive actions of MA, a hydrolysis-stable analog of the endocannabinoid anandamide, and THC, a plant-derived cannabinoid.”
“In conclusion, our results suggest that there exists a signaling pathway by which the binding of cannabinoids to specific receptors leads via intracellular MAPK activation to induction of TIMP-1 expression and subsequent inhibition of tumor cell invasion. To our knowledge, this is the first report of TIMP-1–dependent anti-invasive effects of cannabinoids.”
Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death.
“Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Delta-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis… These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors.”
Cannabis and endocannabinoid modulators: Therapeutic promises and challenges.
“The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.”
“Marijuana and cannabinoids as medicine”
“Although references to potential medicinal properties of cannabis date to ancient times, and despite cannabis being included as a medication in Western pharmacopeias from the nineteenth through the early twentieth centuries, there is still no body of reliable information on possible indications or efficacy. In part, slow progress can be attributed to difficulties in identifying the active ingredients in cannabis; THC was not actually characterized and identified as the main psychoactive substance until 1965. The chemical properties of the cannabinoids, for example their virtual insolubility in water, and the fact that they consist of oily liquids at room temperature has posed further challenges in formulation and administration. Increased governmental concerns about the abuse potential of marijuana and hashish also created a regulatory climate in many Western countries that emphasized the negative properties of these substances and absence of any documented medicinal properties, thus discouraging research into therapeutics.”
“Cultural and attitude changes in the latter half of the twentieth century in many Western countries resulted in large groups of ‘mainstream’ adults and adolescents experimenting with marijuana. The scarcity of obvious acute serious toxic effects, and lack of consistent information on longer-term adverse effects has lead to more recent attitudinal changes in many Western societies that have re-opened the possibility of use of cannabis as a medication.”
Cannabis and the brain.
Abstract
“The active compound in herbal cannabis, Delta(9)-tetrahydrocannabinol, exerts all of its known central effects through the CB(1) cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB(1) receptors and the generation of CB(1) receptor knockout mice. Particularly important classes of neurons that express high levels of CB(1) receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB(1) receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB(1) receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization-induced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.”
Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development.
Abstract
“The endocannabinoid system, including its receptors (CB(1) and CB(2)), endogenous ligands (‘endocannabinoids’), synthesising and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. In addition, the endocannabinoids, notably 2-arachidonyl glycerol, are also present in maternal milk. During three distinct developmental stages (i.e. embryonic implantation, prenatal brain development and postnatal suckling), the endocannabinoid system appears to play an essential role for development and survival. Thus, during early pregnancy, successful embryonic passage through the oviduct and implantation into the uterus both require critical enzymatic control of optimal anandamide levels at the appropriate times and sites. During foetal life, the cannabinoid CB(1) receptor plays a major role in brain development, regulating neural progenitor differentiation into neurones and glia and guiding axonal migration and synaptogenesis. Postnatally, CB(1) receptor blockade interferes with the initiation of milk suckling in mouse pups, by inducing oral motor weakness, which exposes a critical role for CB(1) receptors in the initiation of milk suckling by neonates, possibly by interfering with innervation of the tongue muscles. Manipulating the endocannabinoid system by pre- and/or postnatal administration of cannabinoids or maternal marijuana consumption, has significant, yet subtle effects on the offspring. Thus, alterations in the dopamine, GABA and endocannabinoid systems have been reported while enhanced drug seeking behaviour and impaired executive (prefrontal cortical) function have also been observed. The relatively mild nature of the disruptive effects of prenatal cannabinoids may be understood in the framework of the intricate timing requirements and frequently biphasic effects of the (endo)cannabinoids. In conclusion, the endocannabinoid system plays several key roles in pre- and postnatal development. Future studies should further clarify the mechanisms involved and provide a better understanding of the adverse effects of prenatal exposure, in order to design strategies for the treatment of conditions such as infertility, mental retardation and failure-to-thrive.”
The endocannabinoid-CB(1) receptor system in pre- and postnatal life.
Abstract
“Recent research suggests that the endogenous cannabinoids (“endocannabinoids”) and their cannabinoid receptors have a major influence during pre- and postnatal development. First, high levels of the endocannaboid anandamide and cannabinoid receptors are present in the preimplantation embryo and in the uterus, while a temporary reduction of anandamide levels is essential for embryonal implantation. In women accordingly, an inverse association has been reported between fatty acid amide hydrolase (the anandamide degrading enzyme) in human lymphocytes and miscarriage. Second, CB(1) receptors display a transient presence in white matter areas of the pre- and postnatal nervous system, suggesting a role for CB(1) receptors in brain development. Third, endocannabinoids have been detected in maternal milk and activation of CB(1) receptors appears to be critical for milk sucking by newborn mice, apparently activating oral-motor musculature. Fourth, anandamide has neuroprotectant properties in the developing postnatal brain. Finally, prenatal exposure to the active constituent of marihuana (Delta(9)-tetrahydrocannabinol) or to anandamide affects prefrontal cortical functions, memory and motor and addictive behaviors, suggesting a role for the endocannabinoid CB(1) receptor system in the brain structures which control these functions. Further observations suggest that children may be less prone to psychoactive side effects of Delta(9)-tetrahydrocannabinol or endocannabinoids than adults. The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including “non-organic failure-to-thrive” and cystic fibrosis.”
The endocannabinoid-CB receptor system: Importance for development and in pediatric disease.
Abstract
“Endogenous cannabinoids (endocannabinoids) and their cannabinoid CB1 and CB2 receptors, are present from the early stages of gestation and play a number of vital roles for the developing organism. Although most of these data are collected from animal studies, a role for cannabinoid receptors in the developing human brain has been suggested, based on the detection of “atypically” distributed CB1 receptors in several neural pathways of the fetal brain. In addition, a role for the endocannabinoid system for the human infant is likely, since the endocannabinoid 2-arachidonoyl glycerol has been detected in human milk. Animal research indicates that the Endocannabinoid-CB1 Receptor (‘ECBR’) system fulfills a number of roles in the developing organism: 1. embryonal implantation (requires a temporary and localized reduction in anandamide); 2. in neural development (by the transient presence of CB1 receptors in white matter areas of the nervous system); 3. as a neuroprotectant (anandamide protects the developing brain from trauma-induced neuronal loss); 4. in the initiation of suckling in the newborn (where activation of the CB1 receptors in the neonatal brain is critical for survival). 5. In addition, subtle but definite deficiencies have been described in memory, motor and addictive behaviors and in higher cognitive (‘executive’) function in the human offspring as result of prenatal exposure to marihuana. Therefore, the endocanabinoid-CB1 receptor system may play a role in the development of structures which control these functions, including the nigrostriatal pathway and the prefrontal cortex. From the multitude of roles of the endocannabinoids and their receptors in the developing organism, there are two distinct stages of development, during which proper functioning of the endocannabinoid system seems to be critical for survival: embryonal implantation and neonatal milk sucking. We propose that a dysfunctional Endocannabinoid-CB1 Receptor system in infants with growth failure resulting from an inability to ingest food, may resolve the enigma of “non-organic failure-to-thrive” (NOFTT). Developmental observations suggest further that CB1 receptors develop only gradually during the postnatal period, which correlates with an insensitivity to the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects. Excellent clinical results have previously been reported in pediatric oncology and in case studies of children with severe neurological disease or brain trauma. We suggest cannabinoid treatment for children or young adults with cystic fibrosis in order to achieve an improvement of their health condition including improved food intake and reduced inflammatory exacerbations.”
Cannabinoid signalling in the enteric nervous system.
Abstract
“Cannabinoid signalling is an important mechanism of synaptic modulation in the nervous system. Endogenous cannabinoids (anandamide and 2-arachidonyl-glycerol) are synthesized and released via calcium-activated biosynthetic pathways. Exogenous cannabinoids and endocannabinoids act on CB1 and CB2 receptors. CB1 receptors are neuronal receptors which couple via G-proteins to inhibition of adenylate cyclase or to activation or inhibition of ion channels. CB2 receptors are expressed by immune cells and cannabinoids can suppress immune function. In the central nervous system, the endocannabinoids may function as retrograde signals released by the postsynaptic neuron to inhibit neurotransmitter release from presynaptic nerve terminals. Enteric neurons also express CB receptors. Exogenously applied CB receptor agonists inhibit enteric neuronal activity but it is not clear if endocannabinoids released by enteric neurons can produce similar responses in the enteric nervous system (ENS). In this issue of Neurogastroenterology and Motility, Boesmans et al. show that CB1 receptor activation on myenteric neurons maintained in primary culture can suppress neuronal activity, inhibit synaptic transmission and mitochondrial transport along axons. They also provide initial evidence that myenteric neurons (or other cell types present in the cultures) release endocannabinoids and which activate CB1 receptors constitutively. These data provide new information about targets for cannabinoid signalling in the ENS and highlight the potential importance of CB receptors as drug targets. It is necessary that future work extends these interesting findings to intact tissues and ideally to the in vivo setting.”