Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The principal psychoactive component of marijuana, delta-9-tetrahydrocannabinol (Delta9-THC), suppresses nausea and vomiting in cancer patients caused by chemotherapeutics such as cisplatin. Cisplatin induces vomiting via a number of emetic stimuli, including dopamine. Currently, there is controversy as to whether Delta9-THC can prevent emesis produced by dopaminergic agonists such as apomorphine. The present investigation utilizes the least shrew to evaluate the antiemetic potential and the cannabinoid receptor by which Delta9-THC may prevent emesis produced by four dopamine receptor agonists with differing selectivity for D2 and D3 receptors, i.e., a nonselective dopamine receptor agonist (apomorphine), a D2-preferring receptor agonist (quinpirole), and two D3-preferring receptor agonists (quinelorane and 7-OH DPAT). In addition, relative to its antiemetic doses, the motor suppressive doses of Delta9-THC in dopamine D2/D3-receptor-agonist-treated shrews were also evaluated. Thus, different groups of shrews were injected with either vehicle (V) or varying doses of Delta9-THC [0.5, 1, 2.5, 5, or 10 mg/kg, intraperitoneal (i.p.)] 10 min prior to administration of a 2 mg/kg dose of one of the four cited D2/D3 agonists. Immediately after the last injection, the frequency of vomiting for each shrew was recorded for the next 30 min. To investigate which cannabinoid receptor is involved in the antiemetic action of Delta9-THC, various doses of the CB1 receptor antagonist SR 141716A [0, 5, 10, and 20 mg/kg, subcutaneous (s.c.)] were administered to shrews 10 min prior to an injection of a fully effective antiemetic dose of Delta9-THC (5 mg/kg, i.p.). Ten minutes later, each treated shrew was administered with a 2 mg/kg dose of apomorphine. The emesis frequency was recorded for the next 30 min. For locomotor studies, different groups of shrews received either vehicle or various doses of Delta9-THC (0, 5, 10, 20, or 30 mg/kg) 10 min prior to an injection of vehicle or a 2 mg/kg dose of one of the four D2/D3 receptor agonists. The triad of motor behaviors (spontaneous locomotor activity, total duration of movement, and rearing frequency) were recorded for the next 30 min by a computerized video tracking system. Delta9-THC dose-dependently attenuated the frequency of emesis as well as fully protecting shrews from vomiting produced by each one of the four cited dopamine D2/D3 receptor agonists with ID50s ranging from 1 to 4 mg/kg. SR 141716A reversed the antiemetic activity of Delta9-THC against apomorphine-induced emesis. Delta9-THC also differentially suppressed the triad of motor activities in dopamine D2/D3-receptor-agonist-treated shrews with ID50s ranging from 7 to 21 mg/kg. The results suggest that Delta9-THC prevents emesis via cannabinoid CB1 receptors in a potent and dose-dependent manner in D2/D3-receptor-agonist-treated shrews at doses well below those which cause significant motor depression.
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PMID:Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D2/D3 receptor agonists in the least shrew (Cryptotis parva). 1565 78

Cannabinoids, the active components of Cannabis sativa Linnaeus (marijuana) and their derivatives have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression. Here we show that expression levels of both cannabinoid receptors, CB1 and CB2, are significantly higher in CA-human papillomavirus-10 (virally transformed cells derived from adenocarcinoma of human prostate tissue), and other human prostate cells LNCaP, DUI45, PC3, and CWR22Rnu1 than in human prostate epithelial and PZ-HPV-7 (virally transformed cells derived from normal human prostate tissue) cells. WIN-55,212-2 (mixed CB1/CB2 agonist) treatment with androgen-responsive LNCaP cells resulted in a dose- (1-10 micromol/L) and time-dependent (24-48 hours) inhibition of cell growth, blocking of CB1 and CB2 receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this effect. Extending this observation, we found that WIN-55,212-2 treatment with LNCaP resulted in a dose- (1-10 micromol/L) and time-dependent (24-72 hours) induction of apoptosis (a), decrease in protein and mRNA expression of androgen receptor (b), decrease in intracellular protein and mRNA expression of prostate-specific antigen (c), decrease in secreted prostate-specific antigen levels (d), and decrease in protein expression of proliferation cell nuclear antigen and vascular endothelial growth factor (e). Our results suggest that WIN-55,212-2 or other non-habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.
Cancer Res 2005 Mar 01
PMID:Cannabinoid receptor as a novel target for the treatment of prostate cancer. 1575 56

The bioactive phospholipids, LPA (lysophosphatidic acid) and PA (phosphatidic acid), regulate pivotal processes related to the pathogenesis of cancer. Recently, we cloned a novel type of lipid kinase that phosphorylates monoacylglycerols (such as 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand) and diacylglycerols, to form LPA and PA, respectively. This AGK (acylglycerol kinase) is highly expressed in prostate cancer cell lines and the results reviewed here suggest that AGK might be a critical player in the initiation and progression of prostate cancer. Intriguingly, down-regulation of endogenous AGK inhibited EGF (epidermal growth factor), but not LPA-induced ERK1/2 (extracellular-signal-regulated kinase 1/2) activation and progression through the S-phase of the cell cycle. In this review, we will summarize the evidence demonstrating that AGK amplifies EGF growth signalling pathways that play an important role in the pathophysiology of prostate cancer. Because LPA has long been implicated as an autocrine and paracrine growth stimulatory factor for prostate cancer cells, the identification of this novel lipid kinase that regulates its production could provide new and useful targets for preventive or therapeutic measures.
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PMID:Critical role of acylglycerol kinase in epidermal growth factor-induced mitogenesis of prostate cancer cells. 1624 19

Cannabis is the most widely used illicit drug in the world. Cannabinoids are used therapeutically by some patients as they have analgesic, anti-emetic and appetite stimulant properties which palliate adverse symptoms. Use of these agents in an oncology setting raises the question of whether they act to modulate the effectiveness of concurrently administered anti-cancer drugs. The transporter, P-glycoprotein (P-gp) confers multiple drug resistance (MDR) by effluxing a diverse array of anti-cancer agents. This study was undertaken to examine the effect of cannabinoids on P-gp. Unlike the known P-gp inhibitor, PSC833, short 1h exposure to three plant-derived cannabinoids, cannabinol (CBN), cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid receptor agonist, WIN55, 212-2 (WIN) did not inhibit the efflux of the P-gp substrate Rhodamine 123 (Rh123) in either a drug-selected human T lymphoblastoid leukaemia cell line (CEM/VLB(100)) or in a mouse fibroblast MDR1 transfected cell line (77.1). However, in CEM/VLB(100) cells, prolonged 72 h exposure to the cannabinoids, THC and CBD, decreased P-gp expression to a similar extent as the flavonoid, curcumin (turmeric). This correlated with an increase in intracellular accumulation of Rh123 and enhanced sensitivity of the cells to the cytotoxic actions of the P-gp substrate, vinblastine. Taken together, these results provide preliminary evidence that cannabinoids do not exacerbate P-gp mediated MDR. Further, plant-derived cannabinoids are moderately effective in reversing MDR in CEM/VLB(100) cells by decreasing P-gp expression.
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PMID:The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells. 1645 58

1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson's disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.
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PMID:Implication of cannabinoids in neurological diseases. 1669 78

There are at least two types of cannabinoid receptors, CB1 also named CNR1 and CB2 also named CNR2, both coupled to G proteins. CB1 receptors exist primarily on central and peripheral neurons. CB2 receptors are present mainly on immune cells. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol (2-AG), and 2-archidonyl glyceryl ether. Following their release, endocannabinoids are removed from the extracellular space and then degraded by intracellular enzymic hydrolysis. CB1/CB2 agonists are already used clinically as antiemetic or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilatation that accompanies advanced cirrhosis, and cancer.
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PMID:Therapeutic potential of cannabinoid receptor ligands: current status. 1681 Mar 44

Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue. Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB(2) cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream endoplasmic reticulum stress-related targets activating transcription factor 4 (ATF-4) and TRB3 in Delta(9)-tetrahydrocannabinol-induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.
Cancer Res 2006 Jul 01
PMID:Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. 1681 50

The endocannabinoid system has been shown to modulate key cell-signaling pathways involved in cancer cell growth. In this study, we show that cannabinoid receptor type 1 (CB1) antagonist Rimonabant (SR141716) inhibited human breast cancer cell proliferation, being more effective in highly invasive metastatic MDA-MB-231 cells than in less-invasive T47D and MCF-7 cells. The SR141716 antiproliferative effect was not accompanied by apoptosis or necrosis and was characterized by a G1/S-phase cell cycle arrest, decreased expression of cyclin D and E, and increased levels of cyclin-dependent kinase inhibitor p27KIP1. We have also shown that SR141716 exerted a significant antiproliferative action, in vivo, by reducing the volume of xenograft tumors induced by MDA-MB-231 injection in mice. On the other hand, at the concentration range in which we observed the antiproliferative effect in tumor cells, we did not observe evidence of any genotoxic effect on normal cells. Our data also indicate that the SR141716 antiproliferative effect requires lipid raft/caveolae integrity to occur. Indeed, we found that CB1 receptor (CB1R) is completely displaced from lipid rafts in SR141716-treated MDA-MB-231 cells, and cholesterol depletion by methyl-beta-cyclodextrin strongly prevented SR141716-mediated antiproliferative effect. Taken together, our results suggest that SR141716 inhibits human breast cancer cell growth via a CB1R lipid raft/caveolae-mediated mechanism.
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PMID:The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. 1682 29

How cannabinoids influence immune function has been examined extensively in the last 30 years. Studies on drug-abusing humans and animals, as well as in vitro models employing immune cell cultures, have shown that marijuana, natural and endogenous cannabinoid compounds are immunomodulators. These substances modulate host resistance to bacterial, protozoan and viral infections as well as they can profoundly affect the Th1/Th2 response. Recently, two types of cannabinoid receptor, CB1 and CB2, have been discovered. While CB1 is expressed primarily in the brain, CB2 is peculiar of the immune cells. Cannabinoid receptors have been shown to be involved in some but not all of immune effects. Nevertheless, their identification provides a specific mechanism of action in the attempting to find out how exogenous cannabinoids and endogenous cannabinoid system affect the immune apparatus, strengthen the hypothesis of cannabinoids as immunomodulators. As support to this theory, enough evidence exists to suggest that the cannabinoid system significantly affects almost every component of the immune response machinery and impacts the functioning also of the cytokine network. The evaluation of the biological consequences of these drug-induced cytokine changes has also dramatically become important considering not only the impact of cytokines on immune system per se but also envisaging their influence in cancer, inflammation, autoimmune disease, brain injury, hematopoietic colony formation in which cannabinoids have demonstrated a clear role as important modulators.
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PMID:Cannabinoids, immune system and cytokine network. 1691 39

There is a widespread epidemic of obesity in the United States, which has been associated with an increased risk of diabetes mellitus, cancer, and cardiovascular diseases. Although lifestyle modifications and long-term dietary vigilance remain cornerstones of weight reduction treatment, the continued availability of U.S. Food and Drug Administration-approved pharmacotherapies has expanded the options available for the management of obesity. These agents include anorexiants, thermogenic drugs, and lipid-partitioning drugs. As knowledge regarding the possible causes of obesity increases, there are new drugs under investigation, which include beta3-adrenergic receptor agonists, modifiers of leptin, and cannabinoid receptor-1 antagonists (rimonabant). Also under investigation are antidiabetic agents (metformin, exenatide), anticonvulsant drugs (topiramate, zonisamide), antidepressants (bupropion, fluoxetine), and growth hormones. New targets for pharmacotherapy include uncoupling proteins, fatty acid synthase, neuropeptide Y, melanocortin, ghrelin, various regulatory gut peptides, and ciliary neurotropic factor. Pharmacologic agents are in clinical development that target these substances.
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PMID:Obesity: new perspectives and pharmacotherapies. 1692 65


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