Cannabinoids and cancer
Pharmaceuticals (Basel). Endocannabinoids in Body Weight Control. Horn H(1), Böhme B(2), Dietrich L(3), Koch M(4). Author information: (1)Institute of Anatomy, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.leipzig.de. (2)Institute of Anatomy, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany. Beatrice.Schuetzelt@medizin. uni-leipzig.de. (3)Institute of Anatomy, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. (4)Institute of Anatomy, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo. leipzig.de. Maintenance of body weight is fundamental to maintain one's health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing. Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis. Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects. At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism. Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands. To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects. DOI: 10.3390/ph11020055 PMID: 29849009 2. Pain. Cannabis and cannabinoids for the treatment of people with chronic non-cancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Stockings E(1), Campbell G(1), Hall WD(2)(3), Nielsen S(1), Zagic D(1), Rahman R(1), Murnion B(4)(5), Farrell M(1), Weier M(1), Degenhardt L(1). Author information: (1)National Drug and Alcohol Research Centre UNSW Sydney Sydney NSW Australia. (2)Centre for Youth Substance Abuse ResearchUniversity of Queensland Brisbane Queensland Australia. (3)National Addiction Centre Kings College London London England. (4)Discipline of Addiction Medicine, Faculty of Medicine University of Sydney Sydney NSW Australia. (5)Drug Health Services, Concord Repatriation General Hospital, Sydney Local Health District NSW Health Sydney NSW Australia. This review examines evidence cannabinoids in chronic non-cancer pain (CNCP), and addresses gaps in the literature by: considering differences in outcomes based on cannabinoid type and specific CNCP condition; including all study designs; and following IMMPACT guidelines. MEDLINE, Embase, PsycINFO, CENTRAL and clinicaltrials.gov were searched in July 2017. Analyses were conducted using Revman 5.3 and Stata 15.0. A total of 91 publications containing 104 studies were eligible (n = 9958 participants), including 47 RCTs and 57 observational studies. Forty-eight studies examined neuropathic pain, seven studies examined fibromyalgia, one rheumatoid arthritis, and 48 other CNCP (13 MS-related pain, 6 visceral pain, and 29 samples with mixed or undefined CNCP). Across RCTs, PERs for 30% reduction in pain were 29.0% (cannabinoids) vs 25.9% (placebo), significant effect for cannabinoids, number needed to treat to benefit (NNTB): 24 (95%CI 15-61); for 50% reduction in pain, PERs were 18.2% vs. 14.4%; no significant difference. Pooled change in pain intensity (standardised mean difference: -0.14, 95%CI -0.20, -0.08) was equivalent to 3mm on a 100mm visual analogue scale greater than placebo. In RCTs, PERs for all-cause AEs were 81.2% vs. 66.2%; number needed to treat to harm (NNTH): 6 (95%CI 5-8). There were no significant impacts upon physical or emotional functioning, and low-quality evidence of improved sleep and patient global impression of change. Evidence for effectiveness of cannabinoids in CNCP is limited. Effects suggest NNTB are high, and NNTH low, with limited impact on other domains. It appears unlikely that cannabinoids are highly effective medicines for CNCP. 3. BMC Cancer. Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma. Khan MI(1)(2), Sobocińska AA(3)(4), Brodaczewska KK(3), Zielniok K(5), Gajewska M(5), Kieda C(3), Czarnecka AM(3), Szczylik C(3)(6). Author information: (1)Molecular Oncology Laboratory, Department of Oncology, Military Institute of Medicine, ul. Szaserów 128, 04-141, Warsaw, Poland. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. (2)Department of Otolaryngology - Head & Neck Surgery, Western University, London, ON, N6A 3K7, Canada. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. (3)Molecular Oncology Laboratory, Department of Oncology, Military Institute of Medicine, ul. Szaserów 128, 04-141, Warsaw, Poland. (4)Faculty of Biology, Warsaw University, ul. Miecznikowa 1, 02-096, Warsaw, Poland. (5)Department of Physiological Sciences, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776, Warsaw, Poland. (6)Warsaw Medical University, Żwirki i Wigury 61, 02-091, Warsaw, Poland. BACKGROUND: The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2), comprising the endocannabinoid system (ECS). In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212-2 (WIN-55)] in RCC cell lines. METHODS: Human RCC cell lines were used for this study. The CB 1 and CB 2 gene expression levels were analyzed using real-time PCR. Flow cytometric, immunocytochemical and western blot analyses were performed to confirm CB1 and CB2 receptor protein expression. The anti-proliferative effects of synthetic cannabinoids were investigated on cell viability assay. The CB1 and CB2 receptors were blocked pharmacologically with the antagonists SR141716A and AM-630, respectively, to investigate the effects of the agonists JWH-133 and WIN-55. Cell cycle, apoptosis and LDH-based cytotoxicity were analyzed on cannabinoid-treated RCC cells. RESULTS: The CB1 and CB2 genes expression was shown by real-time PCR and flow cytometric and western blot analysis indicating a higher level of CB2 receptor as compared to CB1 in RCC cells. Immunocytochemical staining also confirmed the expression of the CB1 and CB2 proteins. We also found that the synthetic cannabinoid agonist WIN-55 exerted anti-proliferative and cytotoxic effects by inhibiting the growth of RCC cell lines, while the CB2 agonist JWH-133 did not. Pharmacologically blocking the CB1 and CB2 receptors with their respective antagonists SR141716A and AM-630, followed by the WIN-55 treatment of RCC cells allowed uncovering the involvement of CB2, which led to an arrest in the G0/G1 phase of the cell cycle and apoptosis. CONCLUSIONS: This study elucidated the involvement of CB2 in the in vitro inhibition of RCC cells, and future applications of CB2 agonists in the prevention and management of RCC are discussed. 4. Pain. A peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Zhang H(1), Lund DM(1), Ciccone HA(1), Staatz WD(1), Ibrahim MM(1)(2), Largent-Milnes TM(1), Seltzman HH(3), Spigelman I(4), Vanderah TW(1). Author information: (1)Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA. (2)Department of Anesthesiology, College of Medicine, University of Arizona, Tucson, AZ, USA. (3)Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA. (4)Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, CA, USA. Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain. Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients' quality of life. In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP. Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP. Our studies using a syngeneic murine model of CIBP show that both acute and sustained administration of a peripherally restricted CB1R agonist, 4-{2-[-(1E)-1[(4- propylnaphthalen-1-yl) methylidene]-1H-inden-3-yl] ethyl}morpholin e (PrNMI), significantly alleviated spontaneous pain behaviors in the animals. This analgesic effect by PrNMI can be reversed by a systemic administration but not spinal injection of SR141716, a selective CB1R antagonist. Additionally, the cancer-induced bone loss in the animals was not exacerbated by a repeated administration of PrNMI. Furthermore, catalepsy and hypothermia, the common side effects induced by cannabinoids, were measured at the supra-therapeutic doses of PrNMI tested. PrNMI induced mild sedation, yet no anxiety nor a decrease in limb movements were detected. Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects. Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP. 5. Front Oncol. 2018 Apr 24;8:114. doi: 10.3389/fonc.2018.00114. eCollection 2018. Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids. Yasmin-Karim S(1)(2)(3), Moreau M(2)(3)(4), Mueller R(1)(2)(5), Sinha N(1)(2), Dabney R(6), Herman A(6), Ngwa W(1)(2)(3)(4). Author information: (1)Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States. (2)Dana-Farber Cancer Institute, Boston, MA, United States. (3)Harvard Medical School, Boston, MA, United States. (4)University of Massachusetts Lowell, Lowell, MA, United States. (5)University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. (6)Cannabis Science, Inc., Irvine, CA, United States. Over the years, many in vitro and in vivo studies have shown the antineoplastic effects of cannabinoids (CBDs), with reports advocating for investigations of combination therapy approaches that could better leverage these effects in clinical translation. This study explores the potential of combination approaches employing CBDs with radiotherapy (RT) or smart biomaterials toward enhancing therapeutic efficacy during treatment of pancreatic and lung cancers. In in vitro studies, clonogenic assay results showed greater effective tumor cell killing, when combining CBDs and RT. Meanwhile, in vivo study results revealed major increase in survival when employing smart biomaterials for sustained delivery of CBDs to tumor cells. The significance of these findings, considerations for further research, and viable roadmap to clinical translation are discussed.
