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Cannabinoids: potential antitumoral agents?

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Abstract

Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endo- genous substances - the endocannabinoids - that activate specific cell surface receptors. Cannabi- noids exert palliative effects in cancer patients. For example, they inhibit chemotherapy-induced nausea and vomiting, stimulate appetite and inhibit pain. In addition, cannabinoids inhibit tumor growth in laboratory animals. They do so by modulating key cell signaling pathways, thereby in- ducing antitumoral actions such as the apoptotic death of tumor cells as well as the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds as they can kill tumor cells without significantly affecting the viability of their non-transformed counter- parts. On the basis of these preclinical findings a pilot clinical study of ∆ 9 -tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has recently been run. The fair safety profile of THC, together with its possible growth-inhibiting action on tumor cells, may set the ba- sis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

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... Multiple chemicals in Cannabis, including psychoactive and nonpsychoactive cannabinoids as well as flavonoids, possess antitumor activity. [42][43][44][45] Cannabinoids inhibit tumor initiation, metastasis, vascular adhesiveness, tissue invasiveness, and angiogenesis, while selectively stimulating apoptosis of cancer cells. 3,[42][43][44][46][47][48][49][50][51][52][53][54][55][56] They thus, by multiple mechanisms, inhibit all stages of cancer initiation, development, growth, and spread. ...
... [42][43][44][45] Cannabinoids inhibit tumor initiation, metastasis, vascular adhesiveness, tissue invasiveness, and angiogenesis, while selectively stimulating apoptosis of cancer cells. 3,[42][43][44][46][47][48][49][50][51][52][53][54][55][56] They thus, by multiple mechanisms, inhibit all stages of cancer initiation, development, growth, and spread. As a result, in laboratory studies and animal models, cannabinoids destroy tumors while leaving surrounding cells unharmed. ...
... As a result, in laboratory studies and animal models, cannabinoids destroy tumors while leaving surrounding cells unharmed. [42][43][44] In laboratory studies, cannabinoids in-hibit gliomas, thyroid epithelioma, lymphoma, neuroblastoma, and carcinomas of the oral region, lung, skin, uterus, breast, prostate, pancreas, and colon. [42][43][44][46][47][48][49][50][51][52][53][54][55][56] Hypotheses The impact of Cannabis use on cancer risk will depend on the relative magnitudes of the carcinogenic and antitumor effects, leading to three hypotheses: ...
Article
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Introduction: Cannabis smoke contains carcinogens similar to tobacco, in addition to compounds with antitumor activity. Cannabis use reduces the risk of obesity and cannabinoids inhibit chronic inflammation, known causes of cancer. The net effect of Cannabis use on cancer risk is not known. Objective: To examine the association between Cannabis use and cancer risk in the United States. Methods: Identify and analyze published data on cancer risk in Cannabis users. Results: A total of 55 data points, consisting of risk ratios of cancer in Cannabis users and nonusers, were identified from 34 studies. Of these, 5 did not contain data essential for inclusion in the meta-analysis. The remaining data showed a nonsignificant trend to an association with reduced risk (relative risk [RR]=0.90, p>0.06, N=50) although heterogeneity is high (I2=72.4%). Removal of data with high risk of selection bias (defined as those from North Africa and those that failed to adjust for tobacco) and data with high risk of performance bias (defined as those with fewer than 20 cases or controls among Cannabis users) resulted in an RR <1.0 (RR=0.86, p<0.017, N=24) and large effect size (Hedges g=0.66), but did not decrease heterogeneity (I2=74.9). Of all cancer sites, only testicular cancer showed an RR value >1, although this was not significant and had a negligible effect size (RR=1.12, p=0.3, Hedges g=0.02). Following removal of testicular cancers the remaining data showed a decrease in risk (RR=0.87, p<0.025, N=41). Cancers of the head and neck showed a negative association with cancer risk (RR=0.83, p<0.05), with a large effect size (Hedges g=0.55), but high heterogeneity (I2=79.2%). RR did not reach statistical significance in the remaining cancer site categories (lung, testicular, obesity-associated, other). The data are consistent with a negative association between Cannabis use and nontesticular cancer, but there is low confidence in this result due to high heterogeneity and a paucity of data for many cancer types.
... In the last few decades, growing evidence has reported their ability to impair cancer progression both in vitro and in xenograft models of human cancers. The anti-tumorigenic activities include: (i) inhibition of cancer cells' proliferation and migration, (ii) induction of cancer cell death, (iii) impairment of neoangiogenesis, and (iv) modulation of anti-tumor immune response [1][2][3]. Δ-9tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two best-characterized active components contained in marijuana. THC binds with high affinity both CB1 and CB2, while CBD, which lacks psychotropic activity, mainly interacts with vanilloid receptor 1 (TRPV1). ...
... To date, an increasing number of preclinical studies have reported exciting anticancer properties of cannabinoid-related drugs, both in vitro and in xenograft models of several human cancers, including prostate cancer [1][2][3][4][5][6][7][8][9][10][11][12][13]. Interestingly, cannabinoids have been shown to selectively target tumor cells, which upregulate CBs compared with their healthy counterparts. ...
... Finally, it has been widely demonstrated that alterations in endocannabinoid system correlate with tumor onset and progression [1,2,21,22,53]. Then, we wondered whether in addition to the inhibitory effect triggered by targeting CB1 and CB2 with synthetic agonists, the blocking of endogenous system could affect cancer and stromal reactivity. ...
Article
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Endo-, phyto- and synthetic cannabinoids have been proposed as promising anti-cancer agents able to impair cancer cells’ behavior without affecting their non-transformed counterparts. However, cancer outcome depends not only on cancer cells’ activity, but also on the stromal cells, which coevolve with cancer cells to sustain tumor progression. Here, we show for the first time that cannabinoid treatment impairs the activation and the reactivity of cancer-associated fibroblasts (CAFs), the most represented stromal component of prostate tumor microenvironment. Using prostate cancer-derived CAFs, we demonstrated that WIN 55-212.2 mesylate, a synthetic full agonist of cannabinoid receptors (CBs) 1 and 2, downregulates α-smooth muscle actin and matrix metalloprotease-2 expression, and it inhibits CAF migration, essential features to ensure the activated and reactive CAF phenotype. Furthermore, by impairing stromal reactivity, WIN 55-212.2 mesylate also negatively affects CAF-mediated cancer cells’ invasiveness. Using selective antagonists of CBs, we proved that CAFs response to WIN 55-212.2 mesylate is mainly mediated by CB2. Finally, we suggest that endocannabinoids self-sustain both prostate tumor cells migration and CAFs phenotype by an autocrine loop. Overall, our data strongly support the use of cannabinoids as anti-tumor agents in prostate cancer, since they are able to simultaneously strike both cancer and stromal cells.
... 7,8 The potential benefits of marijuana have been medically proposed to include antiemetic effects, appetite stimulation, cancer treatment, sleep improvement, and pain relief. 2,[9][10][11] However, the medical literature and recommendations for use have been disproportionate to the growing support of its potential uses and benefits in the general public. [12][13][14][15] Although some studies have evaluated the perceptions and attitudes of patients regarding the use of medical marijuana (MM) for various health conditions, there are limited data comparing perceptions of its medicinal use in the cancer population, particularly between patients in legalized and nonlegalized states. ...
... trust in medical profession total, median (IQR) 12(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) 12(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) 12(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) 0.839 Median Santa Clara Strength of Religious Faith, median (IQR) 32 (10-40) 39 (10-40) 36 (10-40) <0.001 Median HADS anxiety, median (IQR) Cut-down, Annoyed, Guilty, Eye-Opener; ESAS, Edmonton Symptom Assessment System; GYN, gynecological; HADS, Hospital Anxiety and Depression Scale; IQR, interquartile range. 35-43 : This survey was designed for this study by the authors to determine different aspects of attitudes and beliefs of patients toward MM. ...
... trust in medical profession total, median (IQR) 12(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) 12(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) 12(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) 0.839 Median Santa Clara Strength of Religious Faith, median (IQR) 32 (10-40) 39 (10-40) 36 (10-40) <0.001 Median HADS anxiety, median (IQR) Cut-down, Annoyed, Guilty, Eye-Opener; ESAS, Edmonton Symptom Assessment System; GYN, gynecological; HADS, Hospital Anxiety and Depression Scale; IQR, interquartile range. 35-43 : This survey was designed for this study by the authors to determine different aspects of attitudes and beliefs of patients toward MM. ...
Article
Background: There is a growing preference for the use of marijuana for medical purposes, despite limited evidence regarding its benefits and potential safety risks. Legalization status may play a role in the attitudes and preferences toward medical marijuana (MM). Objectives: The attitudes and beliefs of cancer patients in a legalized (Arizona) versus nonlegalized state (Texas) regarding medical and recreational legalization and medical usefulness of marijuana were compared. Settings/Subjects: Two hundred adult cancer patients were enrolled from outpatient Palliative Care centers at Banner MD Anderson Cancer Center in Gilbert, AZ (n = 100) and The University of Texas MD Anderson Cancer Center in Houston, TX (n = 100). Design and Measurements: Adult cancer patients seen by the Palliative Care teams in the outpatient centers were evaluated. Various physical and psychosocial assessments were conducted, including a survey of attitudes and beliefs toward marijuana. Results: The majority of individuals support legalization of marijuana for medical use (Arizona 92% [85-97%] vs. Texas 90% [82-95%]; p = 0.81) and belief in its medical usefulness (Arizona 97% [92-99%] vs. Texas 93% [86-97%]; p = 0.33) in both states. Overall, 181 (91%) patients supported legalization for medical purposes whereas 80 (40%) supported it for recreational purposes (p < 0.0001). Patients preferred marijuana over current standard treatments for anxiety (60% [51-68%]; p = 0.003). Patients found to favor legalizing MM were younger (p = 0.027), had worse fatigue (p = 0.015), appetite (p = 0.004), anxiety (p = 0.017), and were Cut Down, Annoyed, Guilty, and Eye Opener-Adapted to Include Drugs (CAGE-AID) positive for alcohol/drugs (p < 0.0001). Conclusion: Cancer patients from both legalized and nonlegalized states supported legalization of marijuana for medical purposes and believed in its medical use. The support for legalization for medical use was significantly higher than for recreational use in both states.
... [33,34] In summary, the action of cannabinoids on CB1 receptor localized in the dorsal vagal complex of the brainstem, the region of the brain that brings about the vomiting reflux, is considered responsible for the antiemetic activity of cannabinoid. [35] Appetite stimulation The preparation of bhang is said to be stimulating while the potent preparation of "ganja/charas" inhibits food uptake. Due to lack of scientific knowledge and accessories, a thorough investigation could not be conducted until 1971. ...
... Chronic pain mostly experienced in cancer patient originates due to the inflammatory reaction caused at the site of injury, leading to release of nociceptive component. [35] Interaction of nociceptive component with nociceptors present at the peripheral of primary nerve fiber leads to the nociceptive neurotransmission which is projected from the spinal cord to various regions of brains such as the thalamus and parabrachial nucleus, leading to pain arousal. [40] Analgesics currently available to treat chronic cancer-associated pain have shown severe side effects with fewer efficacies. ...
Article
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ABSTRACT Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage as observed later due to its emergence as an illegal recreational drug. Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol. EC is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system. Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss. THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals). Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits. The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management. KEY WORDS: 2-Arachidonoylglycerol, analgesic, anandamide, cannabidiol, cannabinoid receptor 1, cannabinoid receptor 2, cannabinol, delta-9-tetrahydrocannabinol, endocannabinoid system
... Cannabinoids used in cancer are best-known for their palliative effects, including reducing nausea and vomiting, alleviating cancer pain, and stimulating appetite [178,179]. It has been argued that cannabinoids can exert anti-tumor effects directly through the inhibition of cell proliferation and induction of apoptosis, or indirectly through the inhibition of angiogenesis, invasion and metastasis [180]. ...
... The antitumor effects of cannabinoids have also been observed in various animal tumor models [180]. In general, an enhanced endocannabinoid system is seen in tumor tissues [179,182,183]. However, the role of upregulated endocannabinoid system activity is still controversial as contrasting results have been reported supporting a proliferative as well as an anti-proliferative role of cannabinoids on cancer cells [180,181]. ...
Article
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The biological effects of cannabinoids, the major constituents of the ancient medicinal plantCannabis sativa(marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
... 17,18 In vitro studies suggest a possible therapeutic role for cannabinoids via the inhibition of tumor proliferation and angiogenesis, induction of tumor cell death, and inhibition of invasiveness and stem cell-like properties of GBM. [19][20][21] While the neuroprotective effects of marijuana have been postulated, [22][23][24] chronic habitual recreational cannabis is associated with potential adverse side effects 25 ; in the brain, these include structural changes and functional impairments that may impact cognition. 26,27 Acutely, marijuana affects the cerebral blood flow 28 with transient changes in attention, memory, and impulse control. ...
... While there is little evidence for this benefit in humans, laboratory studies suggest beneficial impacts on the indices of tumor control. [19][20][21] Whether MM has a therapeutic role in humans awaits results from observational research and randomized trials. ...
Article
Background: Glioma is a devastating primary tumor of the central nervous system with difficult-to-manage symptoms. Cannabis products have been postulated to potentially benefit glioma patients. Recent state legalization allowed investigators an opportunity to study glioma patients' adoption of medical marijuana (MM). Objective: Our goals were to: (1) determine the prevalence of marijuana use, both through physician recommendation and self-medication, and (2) evaluate its perceived risks and benefits in glioma patients. Design: Self-report data were collected and descriptive analyses were conducted. Setting/Subjects: Participants were adult, English-speaking patients undergoing treatment for primary non-recurrent malignant glioma in neuro-oncology clinics at an NCI-designated Comprehensive Cancer Center. Measurements: The survey on MM was adapted from previous research and included questions on knowledge and attitudes toward MM; use, frequency, type, and sourcing of MM; and reasons for use of MM and perceived symptom relief among users. Results: A total of 73 patients were surveyed. The majority of participants were aware that MM was legal in the state, and most reported learning of this through the media. Over 70% of participants reported having considered using MM, and a third reported using marijuana products after their diagnosis. Most received recommendations from friends/family rather than a medical provider, and only half of the users had obtained a physician's recommendation. Users generally reported benefits. Conclusions: With the increasing national conversation that accompanies legalization, glioma patients are pursuing marijuana for the treatment for their symptoms. More research and education is needed to bring health care providers into the conversation.
... Cannabis sativa indicate a potential to inhibit human breast cancer cells and to produce tumor eradications (Fig 5g). The active components of Cannabis sativa are cannabinoids, their derivatives exert palliative effects in cancer patients by preventing nausea, vomiting and pain and also stimulated the appetite and these compounds have also been shown antitumor activity in cell culture and animal models by modulating key cell-signalling pathways (Manuel, 2003) [24] . ...
... Cannabis sativa indicate a potential to inhibit human breast cancer cells and to produce tumor eradications (Fig 5g). The active components of Cannabis sativa are cannabinoids, their derivatives exert palliative effects in cancer patients by preventing nausea, vomiting and pain and also stimulated the appetite and these compounds have also been shown antitumor activity in cell culture and animal models by modulating key cell-signalling pathways (Manuel, 2003) [24] . ...
... 1,2 There has been interest in the use of cannabinoids for the treatment of chemotherapy-related side effects such as cachexia, lethargy, and nausea, but their potential use as an anticancer agent is not well supported. 3,4 Cannabinoids can be classified into plant-derived, endocannabinoids and synthetic groups. 5 Plant-derived cannabinoids are largely the product of Cannabis sativa and Cannabis indica plant species. ...
... 64 Intratumor (IT) administration of low doses of cannabinoids enhances the effectiveness of drug. 4,65,66 A study by Yasmin-Karim et al. revealed that a superior pancreatic cancer treatment outcome could be achieved using the combination of cannabinoids and radiotherapy. 7 Similar findings have been demonstrated in a brain glioma cancer model. ...
Article
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Background: Cannabinoid extracts may have anticancer properties, which can improve cancer treatment outcomes. The aim of this review is to determine the potentially utility of cannabinoids in the treatment of pancreatic cancer. Methods: A literature review focused on the biological effects of cannabinoids in cancer treatment, with a focus on pancreatic cancer, was conducted. In vitro and in vivo studies that investigated the effects of cannabinoids in pancreatic cancer were identified and potential mechanisms of action were assessed. Results: Cannabinol receptors have been identified in pancreatic cancer with several studies showing in vitro antiproliferative and proapoptotic effects. The main active substances found in cannabis plants are cannabidiol (CBD) and tetrahydrocannabinol (THC). There effects are predominately mediated through, but not limited to cannabinoid receptor-1, cannabinoid receptor-2, and G-protein-coupled receptor 55 pathways. In vitro studies consistently demonstrated tumor growth-inhibiting effects with CBD, THC, and synthetic derivatives. Synergistic treatment effects have been shown in two studies with the combination of CBD/synthetic cannabinoid receptor ligands and chemotherapy in xenograft and genetically modified spontaneous pancreatic cancer models. There are, however, no clinical studies to date showing treatment benefits in patients with pancreatic cancer. Conclusions: Cannabinoids may be an effective adjunct for the treatment of pancreatic cancer. Data on the anticancer effectiveness of various cannabinoid formulations, treatment dosing, precise mode of action, and clinical studies are lacking.
... Alzheimer's diseases [12]. Furthermore, various-type cannabinoids have been thoroughly reviewed not only as potential anticancer agents, but also as adjuncts for chemotherapy-induced nausea and vomiting and cancer-related conditions such as chronic pain [12][13][14][15][16][17]. Fig. 2 outlines the increased scientific interest in various-type cannabinoids for cancer and neurological disorders research from 1990 to 2018, which has occurred more or less in tandem with the decriminalisation/ legalisation of marijuana products for medicinal and recreational purposes in several countries. ...
Article
Marijuana (i.e., cannabis) and its derivatives are considered the most commonly used of illicit drugs. Within the last two decades, phytocannabinoids and their synthetic analogues have emerged as potential medicines for the treatment of various disorders via targeting of the endocannabinoid system. Recently, some countries have legalized (medicinal/recreational) cannabis, which now allows for more research to be conducted. Accordingly, sensitive and specific analytical assays are required to identify and quantify these compounds in different human matrices. These analytical approaches were developed using mass spectrometric detection, where LC-MS/MS specifically has become the mainstay for the quantitative analysis of tetrahydrocannabinol and other cannabinoids. This is due to its superior selectivity and sensitivity, and ability to determine free and conjugate analytes within the same analysis. This tabular review of such methods is prefaced by a short overview of the major cannabinoids and some of their physiological actions.
... ECS has been demonstrated to have a role in the regulation of signaling pathways involved in cancer pathogenesis [2,3]. Numerous studies have provided evidence that a deregulation of endocannabinoids production, together with an altered expression of their receptors are hallmarks of cancer [4][5][6]. The role of ECS in the onset of cancer is different and depends on the cancer type and tissue [6]. ...
Article
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Changes in the regulation of endocannabinoid production, together with an altered expression of their receptors are hallmarks of cancer, including colorectal cancer (CRC). Although several studies have been conducted to understand the biological role of the CB1 receptor in cancer, little is known about its involvement in the metastatic process of CRC. The aim of this study was to investigate the possible link between CB1 receptor expression and the presence of metastasis in patients with CRC, investigating the main signaling pathways elicited downstream of CB1 receptor in colon cancer. Fifty-nine consecutive patients, with histologically proven colorectal cancer, were enrolled in the study, of which 30 patients with synchronous metastasis, at first diagnosis and 29 without metastasis. A low expression of CB1 receptor were detected in primary tumor tissue of CRC patients with metastasis and consequently, we observed an alteration of CB1 receptor downstream signaling. These signaling routes were also altered in intestinal normal mucosa, suggesting that, normal mucosa surrounding the tumor provides a realistic picture of the molecules involved in tissue malignant transformation. These observations contribute to the idea that drugs able to induce CB1 receptor expression can be helpful in order to set new anticancer therapeutic strategies.
... Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant with active compounds known as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures, it has beneficial effects in the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis [4][5][6][7]. The discovery of cannabinoid receptors (CB1 and CB2) made important advance in recent years for the investigation of the therapeutic effects of cannabinoids. ...
Article
Purpose: Health concerns around cannabis (marijuana) use have focused on the possible relationship with psychosis and lower airway health, however; the effect of cannabis smoking on upper airway health has received less attention. The aim of this study is to investigate difference between exclusive tobacco cigarettes smoking compared with tobacco plus cannabis smoking regarding severity of chronic rhinosinusitis (CRS). Material and methods: A prospective cross-sectional study with two groups of CRS patients recruited (Group 1: tobacco cigarettes smokers; 100 patients and group 2: tobacco cigarettes smokers and also cannabis users; 100 patients). Recruitment occurred in a general practice in Egypt. Cannabis use was recorded by self-report. Severity of CRS was assessed and compared between 2 groups using SNOT-20 questionnaire, Lund-Mackay CT score and Lund-Kennedy (LK) endoscopy Score. Results: Group 2 patients (tobacco plus cannabis smokers) had significantly higher mean of assessment cores (SNOT-20 (P = 0.005), Lund-Mackay CT score (P = 0.006) and Lund-Kennedy (LK) endoscopy Score (P = 0.005)). Group 2 patients also had significantly higher mean of facial pain/pressure, difficulty sleep, and wake at night, lack of sleep, wake up tired, fatigue, reduced productivity, reduced concentration, frustration/restless/irritable, sad and embarrassed compared to patients in group 1. Conclusion: Adult patients who smoked tobacco cigarettes plus cannabis mixed with tobacco had greater health related quality of life burden and more severe CRS compared to patients who smoked tobacco cigarettes only.
... Nevertheless, additional studies also demonstrated dramatically reduced signs of rimonabant-precipitated withdrawal in mice chronically-treated with PNR-4-20, as compared to mice chronically treated with JWH-018 (Ford et al., 2017). Because FDA-approved cannabinoids like dronabinol and nabilone are utilized for chronic conditions like persistent nausea and wasting syndromes associated with cancer and AIDS (Guzman, 2003), we were here interested in further determining if chronic administration of PNR-4-20 would produce either reduced or less persistent tolerance to cannabinoid-induced effects when compared to unbiased CB1R agonists. Using implantable radiotelemetry probes, we sought to non-invasively assess drug-elicited changes in core temperature over time in the much less stressful environment of the home cage. ...
Article
Most cannabinoid CB1 receptor (CB1R) agonists signal through both G protein-dependent and -independent pathways in an unbiased manner. Recruitment of β-arrestin 2 desensitizes and internalizes receptors, producing tolerance which limits therapeutic utility of cannabinoids for chronic conditions. We developed the indole quinuclidinone (IQD) analogue PNR-4-20 as a novel G protein-biased agonist at CB1Rs, and the present studies determine if repeated administration of PNR-4-20 produces lesser tolerance to in vivo effects as compared to unbiased CB1R agonists Δ9-THC and JWH-018. Adult male NIH Swiss mice were administered comparable doses of PNR-4-20 (100 mg/kg), Δ9-THC (30 mg/kg) or JWH-018 (3 mg/kg) once per day for 5 consecutive days in order to determine tolerance development to hypothermic, antinociceptive and cataleptic effects. Persistence of tolerance was then determined after a drug abstinence period. We found that unbiased CB1R agonists Δ9-THC and JWH-018 produced similar tolerance to these effects, but lesser tolerance was observed with PNR-4-20 for hypothermic and cataleptic effects. Tolerance to the effects of PNR-4-20 completely recovered after drug abstinence, while residual tolerance was always observed with unbiased CB1R agonists. Repeated treatment with PNR-4-20 and Δ9-THC produced asymmetrical cross-tolerance to hypothermic effects. Importantly, binding studies suggest PNR-4-20 produced significantly less downregulation of CB1Rs relative to Δ9-THC in hypothalamus and thalamus of chronically treated mice. These studies suggest that the G protein-biased CB1R agonist PNR-4-20 produces significantly less tolerance than unbiased cannabinoid agonists, and that the IQD analogues should be investigated further as a novel molecular scaffold for development of new therapeutics.
... Thus, illicit and licit cannabinoids are used therapeutically (Bonhomme-Faivre et al. 2008), and more such uses are likely to be found. For example, in vitro and in vivo studies have demonstrated the antiproliferative actions of cannabis on cancers (Guzmán 2003). Clinical studies reported the direct antitumor activity of THC on cancers such as glioblastoma (Guzman et al. 2006), suggesting the clinical relevance of cannabis in cancer treatment. ...
Chapter
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ATP-binding cassette (ABC) transporters are a superfamily of integral membrane proteins located in several places in the human body, including the blood-brain barrier (BBB), and are involved in substrate translocation and tissue protection from harmful substances, including drugs of abuse. A growing body of evidence indicates that the ABC transporters are involved in clinically relevant actions of drugs of abuse, including their primary subjective effects, adverse effects, drug resistance, and drug-drug interactions. Moreover, evidence suggest that drugs of abuse can alter the function and/or expression of these transporters, meaning that ABC transporters influence the distribution of these drugs to the CNS. Opioids, cannabinoids, stimulants, and other classes of abused drugs interact with ABC transporters in various ways. Although there is clearly evidence for a role of ABC transporters in the actions of drugs of abuse, and potentially in drug dependence, the relationship between ABC transporters and drugs of abuse remains understudied and underappreciated. In this chapter, pre-clinical and clinical studies demonstrating the interaction of ABC transporters with drugs of abuse will be explored, with emphasis on their effects on the expression and function of ABC transporters.
... A recent review scrutinised the preclinical and clinical studies for medical use of cannabis [8]. Several reviews outlined the potentiality of cannabinoid as anticancer agents, alleviators of chemotherapy induced nausea and vomiting CINV, and cancer related pain [9][10][11][12][13][14]. Studies of oral or oromucosal cannabinoid spray or even pulmonary administration of cannabis smoke in oncology patients showed its tolerability with dose dependent adverse effects (Table 1). ...
Preprint
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Endocannbinoids system (ECS) engrossed a considerable interest as potential therapeutic targets in various carcinomas and cancer related conditions alongside with neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations, so in this short review we tried to shed the light over the potential drug interactions of medicinal cannabis. Hitherto, few data have been provided to the healthcare practitioners about the drug-drug interactions of cannabinoids with other prescription medications. In general, cannabinoids are usually well tolerated, but the bidirectional effects may be expected with concomitant administered agents via affected membrane transporters (glycoprotein p, breast cancer resistance proteins) and metabolizing enzymes (Cytochrome P450 and UDP- glucuronosyltransferases). The caveats should be undertaken to closely monitor the responses of cannabis users with certain drugs to guard their safety, especially for the elderly and people with chronic diseases or kidney and liver conditions.
... For this reason, the need to continue studies on pharmacological agents preventing and/or treating IRI remains evident. There has also long been interest in the use of cannabis products in the treatment of various medical conditions, including pain [47], multiple sclerosis [48], Huntington's disease [49], stroke [50], atherosclerosis [51,52], inflammatory bowel diseases [53], renal fibrosis [54] and cancer [55]. On the other hand, chronic inflammatory disease of the artery wall and endothelial dysfunction has been proposed as a key mechanism of CV risk [1,6,56,57], and the endocannabinoid system is also thought to be an important signalling pathway in the cardiovascular system [58]. ...
Article
Background: Ischemia/reperfusion (I/R) is a pivotal mechanism of organ injury during clinical stetting for example for cardiopulmonary bypasses. The generation of reactive oxygen species (ROS) during I/R induces oxidative stress that promotes endothelial dysfunction, DNA dissociation and local inflammation. In turn, those processes induce cytokine release, resulting in damage to cellular structures and cell death. One of the major psychoactive compounds of Cannabis is delta-9-tetrahydrocannabinol (Δ9-THC), which is known as an anti-inflammatory mediator. Our research aimed to test if Δ9-THC may be protective in the treatment of cardiovascular system dysfunction arising from I/R heart injury. Methods: Two experimental models were used: isolated rat hearts perfused with the Langendorff method and human cardiac myocytes (HCM) culture. Rat hearts and HCM underwent ex vivo/chemical in vitro I/R protocol with/without Δ9-THC treatment. The following parameters were measured: cell metabolic activity, morphology changes, cell damage as lactate dehydrogenase (LDH) activity, ceramide kinase (CERK) activity, ROS level, total antioxidant capacity (TAC) and heart hemodynamic parameters. Results: Δ9-THC protected the heart, as evidenced by the improved recovery of cardiac function (p < 0.05, N = 3-6). Cells subjected to I/R showed lower cytoplasmic LDH activity, and 10 μM Δ9-THC treatment reduced cell injury and increased LDH content (p = 0.019, N = 6-9). Morphology changes of HCM-spherical shape, vacuolisation of cytoplasm and swollen mitochondria-were inhibited due to Δ9-THC treatment. I/R condition affected cell viability, but 10 μM Δ9-THC decreased the number of dead cells (p = 0.005, N = 6-9). The total level of CERK was lower in the I/R group, reflecting oxidative/nitrosative stress changes. The administration of Δ9-THC effectively increased the production of CERK to the level of aerobic control (p = 0.028, N = 6-9). ROS level was significantly decreased in I/R cells (p = 0.007, N = 6-8), confirming oxidative stress, while administration of 10 μM Δ9-THC enhanced TAC in cardiomyocytes subjected to I/R (p = 0.010, N = 6-8). Conclusions: Δ9-THC promotes the viability of cardiomyocytes, improves their metabolic activity, decreases cell damage and restores heart mechanical function, serving as a cardioprotective. We proposed the use of Δ9-THC as a cardioprotective drug to be, administered before onset of I/R protocol.
... Cannabinoids of Cannabis sativa stimulate appetite and prevent vomiting; pain and nausea in cancer patients so have palliative effects. These compounds also modulate key cellsignalling pathways to inhibit the growth of tumour cells in animal models and culture 62 . ...
Article
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Now a days cancer incidences are in increasing trend and therefore instant effective therapies are needed to control these malignancies. Normally rapidly dividing cells are controlled by anti-cancer drugs, but the normal cells are also affected and pattern in which it is determines the side effects. The way in which the other cells are affected determines the side effects of the individual drugs. These side effects may be minimized by improving and new remedial preparations. These drugs could be of ethno botanical origin. Auspiciously numerous preceding readings have shown that the anti-cancer activities of non-toxic biological macromolecules are higher than conventional chemotherapy drugs. Marine algae is obliged as significant sources of natural bioactive substances and there has now emerged a new proclivity towards isolating and identifying such compounds and constituents from algae. This review article has poised studies about algal anticancer agents.
... There is, however, concern that cannabis products are, paradoxically, implicated in an irrefutable increase in the marijuana hyperemesis syndrome which is usually characterized by at least weekly use of MJ for more than one year [20][21][22][23][24][25][26]. ...
... However, a tumor-suppressive role of ECS was also indicated by some studies, e.g., the upregulation of endocannabinoid-degrading enzymes was observed in aggressive human cancers and cancer cell lines [51]. Moreover, experimental studies showed that the activation of CB receptors by cannabinoids is antitumorigenic in most cases, i.e., it inhibits tumor cell proliferation, induces apoptosis in vitro, and blocks angiogenesis and tumor invasion/metastasis in vivo [35,46,51,52]. The effects of CB receptor (over)expression in selected human tumor cell lines are described in more detail in Table 1. ...
Article
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The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids. The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes. Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer. In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite. In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types. Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries. In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration. Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients. The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.
... Non-psychotropic cannabinoids (Mostly cannabidiol) are also evaluated in many cell lines showing anti-proliferative, anti-angiogenesis action. [18] Combined use of THC and cannabidiol is found to be more effective than THC alone. Combination of different cannabinoids at different proportion could be a better option in the future. ...
Presentation
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Cannabinoids are the organic compounds derived from the flowering top of cannabis plant commonly known as marijuana. Humans' knowledge about the cannabinoids dates back to the period of their own beginnings. These substances have been used by ancient humans for therapeutic and recreational purposes. Considering the lack of acceptable medical use, safety and illicit use, the cultivation of cannabis plant and the use of plant derived compounds was banned in modern history. But the unmet need in the field of treating cancer and neurodegenerative disorders like multiple sclerosis opened the door for the research on cannabinoids. Drugs like nabilone, dronabinol, Sativex have been approved for these indications and Rimonabant, the drug approved for obesity was banned for causing suicidal thoughts and depression. Despite the hide and seek from the researchers, the cannabinoids have been studied in various disorders of CNS, CVS, GIT and Immune system. The growing interest in this field is also due to the better understanding of endogenous cannabinoids system, and its imbalance in disease conditions. In this presentation, the pharmacology of cannabinoids and their therapeutic potential will be discussed under following headings …  Pharmacology of cannabinoids  Endocannabinoid system  Phytocannabinoids  Synthetic analogues  Therapeutic uses Abstract for Subject Review Cannabinoids-Pharmacology and their potential therapeutic applications 1 | P a g e Subject review Cannabinoids-Pharmacology and their potential therapeutic applications  Introduction  Pharmacology of cannabinoids • Phytocannabinoids • Endocannabinoid system • Synthetic analogues  Therapeutic uses
... 115 Although presently absent within otolaryngology literature, there is encouraging in vitro and in vivo data demonstrating significant antineoplastic potential of the ESS within a wide variety of cancer models. 34,38,109,116 The ENT-related tumors with data demonstrating the potential antineoplastic activity of cannabinoids include In addition to the direct effects observed, ESS agonism was also shown to increase paclitaxel induced apoptosis by two-fold via an unknown synergistic mechanism. 7 A summary of data relating to thyroid cancer is shown in Table V. ...
Article
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Objectives 1) review benefits and risks of cannabis use, with emphasis on otolaryngic disease processes; 2) define and review the endocannabinoid signaling system (ESS); and 3) review state and federal regulations for the use and research of cannabis and ESS modulators. Methods This manuscript is a review of the current literature relevant to the stated objectives. Results Cannabis (marijuana) use is increasing. It is the most widely used illicit substance in the world. There is increasing interest in its therapeutic potential due to changing perceptions, new research, and legislation changes controlling its use. The legal classification of cannabis is complicated due to varied and conflicting state and federal laws. There are currently two synthetic cannabinoid drugs that are FDA approved. Current indications for use include chemotherapy‐related nausea and vomiting, cachexia, and appetite loss. Research has demonstrated potential benefit for use in many other pathologies including pain, inflammatory states, and malignancy. Data exists demonstrating potential antineoplastic benefit in oral, thyroid, and skin cancers. Conclusions ESS modulators may play both a causal and therapeutic role in several disorders seen in otolaryngology patients. The use of cannabis and cannabinoids is not without risk. There is a need for further research to better understand both the adverse and therapeutic effects of cannabis use. With increasing rates of consumption, elevated public awareness, and rapidly changing legislation, it is helpful for the otolaryngologist to be aware of both the adverse manifestations of use and the potential therapeutic benefits when talking with patients.
... The endocannabinoid system (ECS) refers to a complex biological web of lipid signaling agents, the cellular receptors they activate, and the enzymes responsible for their biosynthesis and degradation. This system is widely distributed in the brain, immunologic tissue, and other organs, and has myriad effects on basic mammalian functions and disorders ranging from cardiovascular function [10,11], gastrointestinal function [12], liver function [13][14][15], kidney function [16], degenerative neurological disorders [17][18][19], schizophrenia [20], addiction [21], anxiety and depression [22][23][24], pain [25,26], cancer [27][28][29], reproduction [30], bone healing [31,32], and skin disease [33]. Perhaps the best way to approach understanding and defining this system is by reviewing the scientific discoveries that revealed, and are continuing to reveal its complexities. ...
... Two cannabinoid receptors, CB1 and CB2, are distributed in various systems of the human body. CB1 receptors are mainly found in the central nervous system, the uterus, the testes, the eyes, and the spleen, whilst CB2 receptors are associated with organs of the immune system and tumour cells (Pertwee, 2006, Guzman, 2003 (Benjamin and Fossler, 2016). Nabilone is still undergoing clinical trials for approval from the FDA (Haney et al., 2013). ...
Thesis
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There has been a substantial increase, worldwide, in the incidence of thyroid cancer over the past few decades. The diagnosis of thyroid cancer poses a clinical challenge to medical practitioners. Fine needle aspiration cytology (FNAC) is a current standard method to diagnose thyroid cancer. FNAC has a false-positive rate of 1% - 5% and a false-negative rate of 0% - 7.7%, whilst 20% - 30% of cases remain non-diagnostic. Grey-scale ultrasound is a useful imaging technique for the assessment of the thyroid gland, because it can characterize various features of thyroid nodules such as the number, site, size, shape, echogenicity, and internal architecture. However, grey-scale ultrasound has limited value in differentiating benign and malignant thyroid nodules because of its varied sensitivity (52% - 97%) and specificity (26% - 83%). The varied sensitivity and specificity of grey-scale ultrasound might be due to the qualitative analysis and subjective interpretation of the characteristics of thyroid nodules and renders it thus vulnerable to inter- and intra-observer variations. Nevertheless, certain features of thyroid nodules can be quantified, for example tissue stiffness and the vascularity index. Shear wave elastography is a novel ultrasound technique that can quantify tissue stiffness by tracking the propagation of shear waves through thyroid nodules. In general, malignant thyroid nodules tend to be stiffer than benign nodules. Depending upon the differences in stiffness values, thyroid nodules can be differentiated as benign or malignant. The first study of this thesis evaluated the feasibility of using shear wave elastography in predicting thyroid malignancy, and determined if any (and if so, which ones) of the shear wave elastography indices (Emaximum, Emean, and Eminimum) are potential predictors of thyroid malignancy. The study further evaluated the diagnostic accuracy in differentiating benign and malignant thyroid nodules when grey-scale ultrasound was combined with shear wave elastography. Vascularity is a dynamic feature usually detected on Doppler ultrasound. Central vascularity and hypervascularity are usually associated with malignant thyroid nodules. However, not all previous studies appreciate the usefulness of vascularity in predicting thyroid malignancy. Controversial results might be due to the fact that previous studies evaluated vascularity by visual assessment methods that involve subjective interpretation and thus result in high inter- and intra-observer variations. Moreover, in previous studies, the methods used to delineate a border between peripheral and central regions of a thyroid nodule were not standardized. In the second study in this thesis, we have thus developed a computer algorithm that can perform regional segmentation of thyroid nodules by using an 'offsetting' method, and quantify the overall vascularity as well as the vascularity in peripheral and central regions of thyroid nodules. Based on the differences in the vascularity indices, thyroid nodules can be differentiated into benign and malignant types. The study further evaluated the potential advantage of combining the vascularity index with grey-scale ultrasound to enhance the diagnostic accuracy of thyroid malignancy. In the first and second study, a total of 111 patients with solitary thyroid nodules were included. Each thyroid nodule was assessed with grey-scale ultrasound, shear wave elastography, and colour Doppler ultrasound. The diagnosis of the thyroid nodules was confirmed by FNAC and/or histological examination. Grey-scale ultrasound features including microcalcification (malignant: 77.8% versus benign: 7.1%), hypoechoic (92.6% versus 33.3%), irregular margins (55.6% versus 16.7%), and a height-to-width ratio > 1 (59.3% versus 13.1%) were found to be more frequently associated with malignant thyroid nodules than with benign thyroid nodules. The differences were statistically significant (all P < 0.05). Regarding shear wave elastography, the results suggested that Emaximum ≥ 67.3 kPa and Emean ≥ 23.1 kPa are independent predictors of thyroid malignancy. Emaximum was found to be the best adjunct to grey-scale ultrasound. The combination of Emaximum or Emean with grey-scale ultrasound enhanced the diagnostic accuracy of grey-scale ultrasound from 58.5% to 80.2% and 78.4%, respectively (P < 0.05). The results of the vascularity index (VI) quantification showed that a 22% offset was optimal for regional subdivision of thyroid nodules. At the optimum offset, the mean VI of peripheral, central, and overall regions of malignant nodules were significantly higher than those of benign nodules (26.5 ± 16.2%, 21.7 ± 19.6%, 23.8 ± 4.6% versus 18.2 ± 16.7%, 11.9 ± 15.1%, and 16.6 ± 1.8%, respectively, P < 0.05). The optimum cut-off points of peripheral, central, and overall VI were 19.7%, 9.1%, and 20.2%, respectively. When compared to grey-scale ultrasound alone, a combination of VI assessment and grey-scale ultrasound evaluation of thyroid nodules increased the overall diagnostic accuracy from 58.6% to 79.3% (P < 0.05). Studies 1 and 2 have clinical significance in establishing methods for accurate diagnosis of thyroid cancer. The results of Study 1 suggest that shear wave elastography has clinical importance in differentiating benign and malignant thyroid nodules. The combination of grey-scale ultrasound with Emaximum or Emean significantly improved the diagnostic accuracy in predicting thyroid cancer. Study 2 has devised a new method to perform regional segmentation of thyroid nodules and to quantify vascularity in each segment. This approach is objective and standardized to quantify thyroid vascularity and helps in differentiating benign and malignant thyroid nodules. Colour Doppler ultrasound (CDU) and power Doppler ultrasound (PDU) are widely used for detecting the vasculature of tissues or organs. In the thyroid gland, CDU and PDU have been used for the differential diagnosis of, amongst others, Hashimoto's disease, Graves' disease, and Reidel's thyroiditis. Doppler ultrasound has also been used in monitoring treatment responses during therapy of thyroid disorders. However, the detection of blood flow in minute blood vessels or vessels with low blood flow is challenging due to technical limitations of previously developed Doppler ultrasound modalities. Most recently, a new ultrasound technology, namely AngioPLUS (Planewave UltraSensitive™ imaging), provides superb sensitivity in the detection of tissue vascularity. The beauty of this technique is that all colour pixels of the tissue can be reconstructed in a single image. AngioPLUS provides high resolution and 3D wall filtering that allow efficient discrimination between blood flow and other soft tissues by analysing space, time, and amplitude information. Study 3 aimed to evaluate the feasibility of using AngioPLUS imaging in assessing thyroid vascularity when combined with CDU or PDU. The study further evaluated whether the addition of AngioPLUS to CDU or PDU enhances the sensitivity in detecting vasculature of thyroid parenchyma. It also investigated whether there is any asymmetry of vascularity between the right and left thyroid lobes. A total of 45 healthy volunteers underwent grey-scale ultrasound, CDU, CDU+AngioPLUS, PDU, and PDU+AngioPLUS evaluations of both lobes of the thyroid gland. Thyroid vascularity was evaluated using our in-house computer algorithm. The results showed that the combination of CDU+AngioPLUS (14.7 ± 9.4%) and the combination of PDU+AngioPLUS (13.4 ± 9%) had significantly higher thyroid VI than CDU (8.8 ± 7.3%) and PDU (4.7 ± 5.4%) alone (all P < 0.05). No asymmetry was found between the VI of the right and left thyroid lobes (P > 0.05). Study 3 highlights the differences in sensitivity of detecting thyroid vasculature assessed by different Doppler ultrasound modalities. The results suggest that AngioPLUS enhances the detection of vascularity when added to PDU or CDU. The clinical significance of the study lies in the detection of small blood vessels and vessels with low blood flow that may help disease diagnosis and treatment monitoring. Study 4 highlights the scope of chemotherapeutic agents in treating papillary thyroid cancer. Current strategies to treat papillary thyroid cancer are largely based on surgery, where recurrence rate is high (up to 33%). Drug development is a costly and time-consuming process. Moreover, the identification of novel therapeutic targets is challenging. Study 4 introduces the concept of 'repurposing of drugs' that evaluates the therapeutic potential of already approved drugs beyond the scope of their primary clinical usage. Cannabinoids are derivatives of the marijuana plant. They have been used for recreation and to relieve pain. Two cannabinoid receptors (CB1 and CB2) are known to be distributed over different body organs and systems in humans. Cannabinoids receptor expression has been noted in many cancers including breast cancer, prostate cancer, hepatic cancer, lung cancer, and colorectal cancer. Anti-cancer actions, including antiproliferation, antimigration, antiangiogenesis, and apoptosis, have been validated in in vitro experiments in various cancer cell lines. In a recent study, immunohistochemistry analysis of surgical specimens of 87 thyroid nodules demonstrated that CB1 and CB2 receptor expression was more significantly associated with papillary thyroid cancer than with benign thyroid nodules. It was further found that CB2 expression was significantly higher than CB1 receptor expression. In Study 4, the therapeutic potential of CB2 receptor agonist (JWH-133) in treating papillary thyroid cancer was evaluated. A normal thyroid follicular cell line (N-thy-ori-3) was used as the control, and BCPAP was the papillary thyroid cancer cell line used in this study. Both cell lines were treated with JWH-133 at 0, 5, 10, 15, 20, 25, and 30-µM concentrations for 24, 48, and 72 hours. Cellular metabolic activity and cell viability were evaluated using an MTT assay. The results demonstrated that 25 µM was the lethal dose concentration for BCPAP cells at which cell viability was reduced to 50% after the optimal 48 hours of incubation. The results also suggested that BCPAP cells were more sensitive to the JWH-133 as compared with N-thy-ori-3. The cytotoxic effect mediated by JWH-133 was not significantly inhibited by CB2 receptor antagonist SR144528 in both cell lines. The results of the study demonstrated that JWH-133 has a potent cytotoxic effect, more pronounced in a papillary thyroid cancer cell line (BCPAP) than in a normal follicular thyroid cell line (N-thy-ori-3). Study 4 suggests that JWH-133 induces cell death in papillary thyroid cancer cells, whilst the survival of normal thyroid follicular cells can be maintained at an acceptable level.
... Endocannabinoids have been shown to influence diverse pathological processes, including malignancy (2,14,15). Endogenous and exogenous cannabinoids have anti-cancer effects; exogenous cannabinoids and many synthetic agonists for cannabinoid receptors, which mimic the effects of endocannabinoids, have been proposed as potential anti-cancer agents (14,(16)(17)(18)(19)(20). Here, we found that corticosteroids downregulate both mRNA and protein of CB1 and attenuate cannabinoid receptor agonist-induced decrease in U-87 MG cell viability. ...
Article
The endocannabinoid system regulates physiological and pathological conditions, including inflammation and cancer. Recently, emotional and physical stressors were observed to be involved in impairing the endocannabinoid system, which was concomitant with an increase in serum corticosteroids. However, the influence of corticosteroids on the endocannabinoid system has yet to be completely elucidated. The present study investigated the effects of corticosterone, one of the corticosteroids, on the endocannabinoid system in malignant glioblastoma cells in vitro. U-87 MG cells derived from malignant glioblastoma were subjected to corticosterone stimulation and their viability, signal transduction, and endocannabinoid-related gene expression were examined. Corticosterone decreased the mRNA and protein expressions of cyclooxygenase-2. Of note, although endocannabinoids decreased cell viability, corticosterone inhibited the cannabinoid receptor agonist-induced decrease in cell viability by downregulating the mRNA and protein expressions of cannabinoid receptor 1 (CB1) in glioblastoma cells. These results suggest that corticosteroids modify the endocannabinoid system in glioblastoma cells, and a reduction in the beneficial anti-tumor effects of endocannabinoids through downregulation of the CB1 receptor by corticosterone may promote the malignant phenotype of glioblastoma.
... Cannabinoids have a huge therapeutic potential: the are anti-bacterial and neuro-protective, inhibit cancer cell growth, promote bone growth, reduce convulsions and seizures, reduce blood sugar levels, etc., see [1,2,3,4,5]. A number of clinical studies indicate that cannabinoids are effective in easing symptoms of a wide range of difficult-tocontrol conditions, including epilepsy, schizophrenia, tumours, diabetes, and many other conditions, see for example [6,7,8,9,10,11,12]. However, currently there is no integrated platform which would collect all the data from diverse clinical studies, academic publications, patients' feedback, etc. ...
Article
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The paper presents an open source platform to integrate and analyse the cannabinoids research data gathered from academic publications, industrial and clinical trials as well as patients. The project focuses on the analysis of the usability aspects important for the applications collecting the treatment data as well as data on diverse cannabinoids strains. The collected data will be used to estimate the efficiency of cannabinoid treatment of various disorders, which will provide an evidence-based assistance for doctors, researchers and industry to identify the right cannabinoid profiles for various conditions.
... It does so by preventing nausea, vomiting, and pain and also stimulates the appetite. These compounds also exhibit antitumor activity in cell culture and animal models by modulating key cell signaling pathways [30]. ...
Article
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Natural products continue to be a source for the discovery of drugs and drug leads even from ancient period. 80% of drug molecules have been obtained from either natural products or derivatives of the natural product. It has been found that the concept of a single drug for treating single disease may become outdated in the near future and the need of polyherbal formulations, as an alternate remedy is under investigation. Medicinal and aromatic plants contain biologically important phytochemicals, which have known curative properties. They are found as secondary metabolites in plants. Plants also contain certain other compounds that moderate the effects of the active ingredients. Medicinal and aromatic plants have their own contribution toward the treatment of both noncommunicable and communicable diseases. A survey done by the WHO indicates that a majority of the world population tends to use plants for treating diseases. Cancer, the second largest cause of death after cardiovascular disease accounts for about 3500 million people globally. Due to the serious side effects of synthetic chemopreventive agents, research is going onto investigate the nature derived chemopreventive agents. In addition to the plant-derived compounds, marine, and animal resources also play an important role as clinically beneficial anticancer agents with minimal or no toxicity. The best examples for plant-derived compounds include vincristine, vinblastine, irinotecan, etoposide, and paclitaxel; they have a different mode of action against cancer such as interaction with microtubules, inhibition of topoisomerases I or II, alkylation of DNA, and interference with tumor signal transduction. The natural products from marine sources such as bryostatin, squalamine exhibit a significant antimitotic, and anti-angiogenic activities. The benefits of various anticancer drugs derived from natural products are the fact that it can have its effect on cancer cells alone without harming healthy cells, which is unlikely to be the case with other conventional chemotherapeutics. In this review, various natural products and their anticancer properties have been discussed briefly.
... Otro aspecto fundamental a tratar, es el efecto psicoactivo que tienen los cannabinoides en humanos 25 . Estos compuesto ejercen una variedad única de efectos excitatorios e inhibitorios en el sistema nervioso central, que pueden ser divididos en 4 grupos: afectivos, sensoriales, somáticos y cognitivos. ...
Article
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The objective of this review is to check the possibility and plausibility of using selective cannabinoid agonists/antagonists as antitumor drugs, because the neoplastic cells have demonstrated an altered expression of these ligands. Based on the study of the endocannabinoid system and its relevance as a superior homeostatic modulator in different brain functions or cognitive ones, various lines of research started studying the mechanisms of action and cellular response of the cannabinoid receptors type 1 and type 2. In this respect it has been shown that the cannabinoid receptor agonist drugs (cannabimemetic) are capable of inhibiting mitosis of cancer cells. Multiple studies in various cancer cells, where a xenotransplant is done in rats with tumor from human cells, they show a decrease in cell growth, dose-dependent effect, thus as on the viability of cancer cells. Is completely encouraging to study more thoroughly this new therapeutic approach against cancer, the impact that might have to deploy synergistic therapies based on cannabinoids and chemotherapy against the most prevalent malignancies in the world, could offer a more complete treatment. This review checks the neoplasm that are sensitive to be treated with cannabinoids, the endocannabinoide system in cancer, the adverse effects of the cannabinoids in cancer, and the most relevant studies that justify this new therapeutic approach against cancer.
... Cannabis sativa extract not only kills cancer cells, but it also helps with chemotherapy side effects including nausea and vomiting (Guzm an, 2003). Findings suggested that CBD could suppress the activation of the EGF signaling pathway indicating their ability to inhibit proinflammatory pathways (Elbaz et al., 2015). ...
Article
Marijuana, or Cannabis sativa L., is a common psychoactive plant used for both recreational and medicinal purposes. In many countries, cannabis-based medicines have been legalized under certain conditions because of their immense prospects in medicinal applications. With a comprehensive insight into the prospects and challenges associated with the pharmacological use and global trade of C. sativa, this mini-review focuses on the medicinal importance of the plant and its legal status worldwide; the pharmacological compounds and its therapeutic potential along with the underlying public health concerns and future perspective are herein discussed. The existence of major compounds including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, cannabinol, and cannabichromene contributes to the medicinal effects of the cannabis plant. These compounds are also involved in the treatment of various types of cancer, epilepsy, and Parkinson's disease displaying several mechanisms of action. Cannabis sativa is a plant with significant pharmacological potential. However, several aspects of the plant need an in-depth understanding of the drug mechanism and its interaction with other drugs. Only after addressing these health concerns, legalization of cannabis could be utilized to its full potential as a future medicine.
... The extracts from Anacardium occidentale have been reported to have prophylactic, anesthetic, bactericidal and insecticidal properties [21] as well as anti-tumour and antioxidant potentials. Numerous studies have provided evidence that cannabinoids from Cannabis sativa exhibit antitumor effects in a wide array of animal models of cancer [22,23]. ...
Article
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Topoisomerase II alpha catalyses and guides the unknotting of DNA by creating double transient breaks in the DNA using a conserved tyrosine as the catalytic residue. Topoisomerase II alpha has been shown to be overexpressed in numerous types of cancers and it is a target for multiple chemotherapeutic agents. Many DNA topoisomerase inhibitors have been identified from natural sources and have been reviewed in many reports as anticancer agents. In the present study, a total of 240 phytochemicals characterized from four reported anticancer plants (Anacardium occidentale, Andrographis paniculata, Cannabis sativa and Tinospora cordifolia) were obtained from literatures and screened against the binding pocket of topoisomerase II alpha. From the pool of phytochemicals only 7-o-methylcyanidin, 20-betaecdysone, Andropanoside and Palmatoside-G qualified as Phyto-compounds with good oral bioactivity when subjected to the Lipinski’s rule of five. Bioassay data containing the IC50 of compounds screened against topoisomerase II alpha was used to generate a regression model using the 3D-QSAR techniques. A very viable model with R2 = 0.954, adjusted R2 = 0.908, Pearson R = 0.977, cross validation Q2 = 0.851, Standard Error of Estimate = 0.125, F = (20.803, p < 0.05) and Durbin-Watson constant = 1.613 was obtained. The 3D-QSAR result shows that Andropanoside and 20-betaecdysone may be better inhibitors of topoisomerase II alpha catalytic site than the standard drug, Etoposide. To further confirm this, the molecular interactions of Andropanoside and 20-betaecdysone were compared to those of Etoposide using the ligand interaction interface of Maestro environment.
... Traditional chemotherapies generate toxicity, but Cannabinoids over come side effect produced by chemotherapic treatment. They also modulate cell signaling pathways and to suppress the tumor cells growth in animal models and cultureline (Guzman, 2003). ...
... Melck et al., 2000;De Petrocellis et al., 1998). It has been reported that cannabinoids can act through different cellular mechanisms by inducing apoptosis, cellcycle arrest, or cell growth inhibition, targeting angiogenesis and cell migration (Bifulco & Di Marzo, 2002;Guzman, 2003;Kogan, 2005). ...
Article
Cannabis sativa contains promising groups of cannabinoids with reported anticancer properties. For the evaluation of pharmacognostical, phytochemical and pharmacological potentials, the herb was collected from the Department of Narcotics Control, Government of Bangladesh. The plant material was extracted with hexane, ethylacetate, methanol and water separately using sohxlet apparatus. The macroscopic and microscopic examinations of the plant sample followed by phytochemical screenings of different solvent extracts showed the presence of flavonoids, phenols, sterols and terpenoids in major. The extracts were further studied for biological screening in brine shrimp lethality as a mean of anticancer activity using vincristine sulfate as positive standard. The LC50 of the hexane part (0.398±0.001 μg/ml) and ethyacetate extract (0.450±0.003 μg/ml) exhibited potential activity in comparison to vincristine sulfate (0.316±0.002 μg/ml). The LC50 values of hexane and ethyacetate extracts are indicative for anticancer activity, and the presence of terpinoids like compounds in those extracts are indicative of potential functionality of cannabinoids like compounds.
... 18,19 It has been reported that cannabinoids can act through different cellular mechanisms by inducing apoptosis, cell-cycle arrest, or cell growth inhibition, targeting angiogenesis and cell migration. [20][21][22] In-silico screening techniques from the compound databases is presently the most popular and useful cheminformatics application in the field of drug discovery. In the current approach, the cannabinoids from the plant, C. sativa as a source of a lead molecule, was used for development of an aromatase inhibitor via computer based analytical techniques using ligand-based molecular docking, drug-like property analysis and ADMET prediction studies and we, here in, report the results of our in silico and laboratory-based studies. ...
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Inhibition of aromatase (CYTP450), a key enzyme in the estrogen biosynthesis, could result in regression of estrogen-dependent tumors and even prevent the promotion of breast cancer. The present research has been designed for searching a potent chemical moiety from natural sources to inhibit aromatase enzyme, the overfunctionality of which causes the breast cancer. Cannabis sativa contains a very much promising group of cannabinoids with more than 66 compounds with reported anticancer property and for the search of a target specific potent aromatase inhibitor, 61 cannabinoids from C. sativa were selected. The Structures Data File (SDF) of these ligand molecules were subjected to docking studies at the binding site of aromatase X-ray crystallographic structure based on lower resolution of the protein crystal structure and higher docking accuracy, predicted by calculating the correlation between experimental activities and Glide dock scores and compared with the standard aromatase ligand androstenedione and aromatase inhibitor fadrozole with existing drug for breast cancer treatment. The best docked pose of each ligand was selected on the basis of the highest dock score related to the binding free energies of the internal dataset compounds as compared to their observed activities. Apart from the hydrogen bond formation with the oxygen present on the aromatic ring system, the other parts of the molecules are stabilized by hydrophobic interactions with non-polar amino acid residues (Ile133, Phe134, Phe221, Trp224, Ile305, Ala306, Ala307, Val369, Val370, Leu372, Val373, Met374 and Leu477). From the screening results of the cannabinoid analogs, 21 out of 61 were found to have an acceptable docking score in comparison to the standards, androstenedione and fadrozole. The pharmacokinetic filters like absorption, distribution, metabolism and excretion and toxicity (ADMET) property determination were applied to select drug-like compounds. Among them three compounds were found to reveal the most promising drug like activity, which were cannabidiorcol (CN 17, CBD-C1), cannabitriol (CN 43, CBT) and cannabiripsol (CN 55, CBR). The ani-cancer activity of the target compounds was performed against brine shrimp lethality biassay, where cannabidiorcol exhibited significant LC50 value of 0.348 ±0.002 μg/ml (R² = 0.9853) which is almost similar to vincristine sulfate (LC50 = 0.316±0.003 μg/ml, R² = 0.9882). Compound cannabitriol also showed promisimg cytotoxicity 0.650±0.004 μg/ml (R² = 0.9882) in comparison to the reference standard. But cannabiripsol demostrated relatively weaker activity 12.95±1.234 μg/ml (R²=0.9897). It can be concluded that the lead compounds may be developed as potent aromatase inhibitor performing their further biological evaluation. Dhaka Univ. J. Pharm. Sci. 19(1): 47-58, 2020 (June)
... De plus, l'intensité de l'immunoréactivité CB1R positive est très marquée dans les couches II/III du CPF . CB1R est également exprimé par les cellules gliales (astrocytes, microglies et oligodendrocytes) mais dans des proportions plus faibles (10 à 100 fois moins que dans les neurones) (Arevalo- Martin et al., 2003;Guzman, 2003;Carrier et al., 2004). L'utilisation de souris transgéniques CB1R -/a permis de mettre en évidence que ces récepteurs sont exclusivement localisés dans les boutons présynaptiques des neurones excitateurs (Glutamate) et inhibiteurs (GABA pour acide gamma-aminobutyrique) (Freund et al., 2003). ...
Thesis
Un faible apport alimentaire en acides gras polyinsaturés (AGPI) de la série n-3 a été associé à la prévalence des troubles de l'humeur chez l’Homme. Chez les rongeurs, les approches nutritionnelles visant à modéliser une alimentation pauvre en AGPI n-3 ont largement été développées au siècle dernier. En effet, un régime alimentaire carencé en AGPI n-3 sur une ou plusieurs générations induit chez le rongeur des altérations des comportements émotionnels tels que des comportements de type dépressif ou anxieux. Nous avons montré au laboratoire Nutrineuro que des souris nourries avec un régime déficient en AGPI n-3 présentent des niveaux d’AGPI n-3, en particulier l'acide docosahexaénoïque (DHA, un AGPI n-3) plus faible dans le cortex préfrontal (PFC) et dans le noyau accumbens (NAc) par rapport aux souris contrôle. De plus, nous avons pu mettre en évidence qu’une alimentation déficiente en AGPI n-3 est capable de moduler la plasticité synaptique dépendante du système endocannabinoïde (eCB). De fait, la réduction de DHA dans le CPF et le NAc est accompagnée d'une altération de la dépression à long terme (LTD-eCB) et des voies de signalisation dépendantes du système eCB au niveau du CPF (Lafourcade et al., 2011 ; Larrieu et al, 2012). Nos données indiquent que ces altérations sont dues à un découplage entre le récepteur cannabinoïde 1 (CB1R) et la protéine Gi/o. De plus, les souris déficientes en AGPI n-3 présentent des déficits comportementaux dans plusieurs tests évaluant les comportements émotionnels. Afin de mieux comprendre les mécanismes qui sous-tendent la diminution du DHA dans le CPF et les altérations des comportements émotionnels, nous avons étudié la morphologie neuronale dans le CPF et l’axe hypothalamo-hypophysaire (HPA) chez les souris déficientes en AGPI n-3. Nous avons montré que le régime alimentaire déficient en AGPI n-3 induit une atrophie de l’arborisation dendritique dans les neurones pyramidaux du CPF. L'atrophie dendritique est semblable à celle mesurée chez les souris soumises au régime équilibré en AGPI n-3 et soumises à un stress chronique de défaite sociale (CSDS). Aucun effet additionnel du CSDS sur la morphologie neuronale et le comportement émotionnel n’a été observé chez les souris déficientes en AGPI n-3. Nous avons ensuite étudié le rôle de l’axe HPA dans le développement des altérations comportementales et neurobiologiques chez les souris déficientes en AGPI n-3. Ces souris présentent une diminution de l'expression des récepteurs des glucocorticoïdes (GR) dans le CPF associée à une augmentation des taux circulants de corticostérone. Dans leur ensemble, nos résultats montrent qu’un faible apport alimentaire en AGPI n-3 peut modifier la plasticité synaptique dépendante du système eCB ainsi que l’arborisation dendritique des neurones du CPF. Nous avons également pu montrer que l’élévation des niveaux de corticostérone était impliquée dans l’altération des comportements émotionnels observée chez des souris nourries avec un régime déficient en AGPI n-3.
... In 2018, Begum et al. reported the presence of anticancer agents Δ 9tetrahydrocannabinol, myrcene (4.1, Figure 4), and linalool (4.2, Figure 4) in Cannabis Sativa (also widely known as Marijuana, Bhang, Ganja, and Hashish). [29][30][31] Galve-Roperh and colleagues showed that Δ 9 -tetrahydrocannabinol, the active component of marijuana, persuades apoptosis of transformed neural cells in in-vitro; where, the study with two subclones of C6 glioma cells in culture confers that cannabinoids indicate apoptosis through the cannabinoid receptors-associated pathway, endured ceramide acquisition and activation of Raf1/extracellular signal-regulated kinase. 32 Colchicaceae. ...
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Chapter
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Thesis
In dieser Arbeit wurde ein Verfahren zur effizienten Herstellung von (−)-trans-Cannabidiol (CBD, 10), (−)-trans-Δ9-Tetrahydrocannabinol (Dronabinol, 21) und (−)-trans-Cannabidivarin (CBDV, 30) durch kontinuierliche Synthese untersucht und entwickelt. CBD konnte durch kontinuierliche Synthese in drei Schritten aus Olivetolcarbonsäuremethylester (OM, 6) und Menthadienol G (3) mit einer Ausbeute von 41 % synthetisiert werden. Bei optimierten Bedingungen betrug die Reinheit nach Kristallisation > 99 %. Die Stereochemie konnte durch Röntgenstrukturanalyse eindeutig als 1R,6R bestimmt werden. Vorteilhaft war dabei, dass Toluol anstatt eines chlorierten Lösungsmittels verwendet werden konnte. Weitere Vorteile waren die kurze Reaktionszeit und die Tatsache, dass die Synthese bei Raumtemperatur durchgeführt werden konnte. Es konnten fünf Nebenprodukte detektiert und identifiziert werden, wovon eines Dronabinol war. Bei optimierten Reaktionsparametern konnte eine Ausbeute an Dronabinol von 64,5 % erreicht werden. Durch Simulated Moving Bed (SMB)-Chromatographie konnte Dronabinol kontinuierlich mit einem Gehalt von > 95 % hergestellt werden. Nach der Synthese waren vier Verunreinigungen detektierbar, und zwar Olivetol (17), CBD, Exo-Tetrahydrocannabinol (Exo-THC, 23) und Δ8-Tetrahydrocannabinol (Δ8-THC, 22). Durch die SMB-Aufreinigung konnten alle Verunreinigungen auf einen monographiekonformen (USP 37) Gehalt abgereichert werden. Nach der finalen destillativen Aufarbeitung trat eine noch nicht identifizierte Verunreinigung in einem Gehalt von ca. 0,4 Flächen-% auf. CBDV konnte durch kontinuierliche Synthese in drei Schritten aus Divarincarbonsäuremethylester (DM, 25) und Menthadienol G synthetisiert werden. Die Ausbeute betrug ca. 30 %, die Reinheit nach Kristallisation > 99 %. Es konnten fünf Nebenprodukte detektiert werden, die im Rahmen dieser Arbeit nicht weiter charakterisiert wurden. Der Syntheseweg bietet durch Modifikation der Seitengruppen an Position 6 (R1) und Position 5 (R2) der Alkylbenzol-Gruppe Zugang zu synthetischen Cannabinoiden mit einem CBD- oder CBDV-Grundgerüst. Es wurden neun neue Cannabinoide hergestellt: 2-Hydroxyethylcannabidiolat (2-HEC, 31), 2-Hydroxypentylcannabidiolat (2 HPC, 32), Glycerylcannabidiolat (GCBD, 33), Cyclohexylcannabidiolat (CHC, 34), Hexylcannabidiolat (HC, 35), N-Methylsulfonylcannabidiolat (NMSC, 36), 2 Hydroxyethylcannabidivarinolat (2-HECBDV, 37), Cyclohexylcannabidivarinolat (CHCBDV, 38) und Hexylcannabidivarinolat (HCBDV, 39). Die Bindungsaffinität wurde in Cannabinoid-Rezeptor-transfizierten HEK293EBNA-Zellen untersucht, die intrinsische Aktivität in CHO-Zellen, die Induktion von NF-κB (nuclear factor kappa B) sowie von NFAT (nuclear factor of activated T cells) in Jurkat-T Zellen, die Induktion proinflammatorischer Zytokine und Chemokine (Interleukin(IL)-6, IL-1β, CC Chemokinligand 2' (CCL2) und Tumornekrosefaktor(TNF)-α) auf mRNA-Ebene in RAW264.7-Makrophagen und die Expression von proinflammatorischen Zytokinen (IL-1β, IL-6, IL-8, TNF-α) und Prostaglandin E2 (PGE2) auf Proteinebene in primären humanen Monozyten. Die CBD-Derivate zeigten eine höhere Selektivität für CB2-Rezeptoren. Die CBDV-Derivate HCBDV und CHCBDV zeigten eine spezifische Bindung an CB1- und CB2-Rezeptoren im nanomolaren Bereich. 2-HEC, 2-HPC, GCBD und NMSC wirkten als Agonisten an CB2- und als Antagonisten am CB1-Rezeptor. CHC band an CB1 und CB2 im submikromolaren Bereich und schien ein Agonist für beide Rezeptoren zu sein. 2- HECBD wirkte als Agonist auf CB2-Rezeptoren und als Antagonist auf CB1-Rezeptoren. In Jurkat-T Zellen hemmte NMSC dosisabhängig die Aktivität von NF-κB sowie von NFAT. 2-HEC, 2-HPC und GCBD hemmten die Expression von NFAT ebenfalls dosisabhängig. CHC und HC reduzierten dosisabhängig die Expression von IL-1β- und CCL2-mRNA in RAW264.7-Makrophagen. NMSC hemmte in geringeren Dosen IL-1β, CCL2 sowie TNF-α und induzierte in höheren Dosen einen starken Anstieg der IL-6-mRNA. In primären humanen Monozyten hemmten 2 HEC und GCBD konzentrationsabhängig die Synthese von IL-1β, IL-6 und TNF-α. 2-HPC hemmte dosisabhängig die Bildung von TNF-α und IL-6. HC verminderte dosisabhängig die Freisetzung von TNF-α und IL-6. NMSC steigerte die durch LPS erhöhte Freisetzung von IL-1β noch weiter, hemmte aber TNF-α, IL-8 und PGE2. Die hier untersuchten CBD- und CBDV-Derivate sind geeignet, gezielt an Cannabinoid-Rezeptoren zu wirken. Einige der Derivate könnten als selektive CB2-Agonisten genutzt werden. Die Länge des aliphatischen Rests an R2 von CBD (Pentyl-Cannabinoiden) und CBDV (Propyl-Cannabinoiden) korrelierte nicht mit der Bindungsaffinität. Eine höhere Polarität an R1 (2-HECBDV > NMSC > GCBD > 2-HEC) schien demgegenüber die agonistische Aktivität an CB2 zu begünstigen. Um den Ergebnissen zur Beziehung zwischen Struktur und Wirkung noch mehr Bedeutung zu geben, wären weitere synthetische Derivate und deren Testung notwendig.
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Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures1–4 and ultra-large libraries of virtual compounds5,6. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries⁷, new approaches to compound screening are needed8,9. Here we introduce a modular synthon-based approach—V-SYNTHES—to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold–synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant (Ki) = 0.9 nM) and CB2/CB1 selectivity (50–200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm.
Thesis
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The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities.
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Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.
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This review discusses three different associations between cannabinoids and cancer. First, it assesses evidence that smoking of cannabis preparations may cause cancers of the aerodigestive and respiratory system. There have been case reports of upper-respiratory-tract cancers in young adults who smoke cannabis, but evidence from a few epidemiological cohort studies and case-control studies is inconsistent. Second, there is mixed evidence on the effects of THC and other cannabinoids on cancers: in some in vitro and in vivo studies THC and some synthetic cannabinoids have had antineoplastic effects, but in other studies THC seems to impair the immune response to cancer. As yet there is no evidence that THC or other cannabinoids have anticancer effects in humans. Third, Delta(9)-tetrahydrocannabinol (THC) may treat the symptoms and side-effects of cancer, and there is evidence that it and other cannabinoids may be useful adjuvant treatments that improve appetite, reduce nausea and vomiting, and alleviate moderate neuropathic pain in patients with cancer. The main challenge for the medical use of cannabinoids is the development of safe and effective methods of use that lead to therapeutic effects but that avoid adverse psychoactive effects. Furthermore, medical, legal, and regulatory obstacles hinder the smoking of cannabis for medical purposes. These very different uses of cannabinoids are in danger of being confused in public debate, especially in the USA where some advocates for the medical use of cannabinoids have argued for smoked cannabis rather than pharmaceutical cannabinoids. We review the available evidence on these three issues and consider their implications for policy.
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Malignant gliomas, including the most common subtype, glioblastoma multiforme (GBM), are among the most devastating of neoplasms. Their aggressive infiltration in the CNS typically produces progressive and profound disability--ultimately leading to death in nearly all cases. Improvement in outcome has been elusive despite decades of intensive clinical and laboratory research. Surgery and radiotherapy, the traditional cornerstones of therapy, provide palliative benefit, while the value of chemotherapy has been marginal and controversial. Limited delivery and tumor heterogeneity are two fundamental factors that have critically hindered therapeutic progress. A novel chemoradiotherapy approach, consisting of temozolomide administered concurrently during radiotherapy followed by adjuvant systemic temozolomide, has recently demonstrated a meaningful, albeit modest, improvement in overall survival for newly diagnosed GBM patients. As cell-signaling alterations linked to the development and progression of gliomas are being increasingly elucidated, targeted therapies have rapidly entered preclinical and clinical evaluation. Responses to therapies that function via DNA damage have been associated with specific mediators of resistance that may also be subject to targeted therapies. Other approaches include novel locoregional delivery techniques to overcome barriers of delivery. The simultaneous development of multiple advanced therapies based on specific tumor biology may finally offer glioma patients improved survival.
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One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.
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