{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:24:16Z","timestamp":1784543056344,"version":"3.55.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Cannabinoid-based therapies are increasingly being used by cancer patients to treat chemotherapy-induced nausea and vomiting. Recently, cannabinoids have gained increased attention for their effects on cancer growth. Indeed, the effect of CB<jats:sub>2<\/jats:sub> (JWH-015, JWH-133) agonists on breast cancer models have shown to reduce the size of breast cancer tumors. However, these studies assessing breast cancer progression were using CB<jats:sub>2<\/jats:sub> agonist administered early into the cancer progression therefore assessing their effects on already established tumors is a critical need. In our study, we evaluate tumor growth using an ectopic xenograft ovarian (SKOV-3 and OVCAR-5) cancer model. The impact of chronic (30\u00a0days) administration of CB<jats:sub>2<\/jats:sub> (JWH-133) agonist will be evaluated and started on 30 days of ectopic ovarian tumors. We will then evaluate and determine the mechanisms involved in ovarian cancer tumor growth by measuring levels of anandamide and 2-arachidonoyl glycerol as well as protein levels of CB<jats:sub>1<\/jats:sub>, CB<jats:sub>2<\/jats:sub>, ER\u03b1, ER\u03b2, GPER, TNF\u03b1, IL-1\u03b2 and IL-6 in ovarian and tumor tissues. Our results demonstrate a significant increase in ectopic ovarian tumor growth following chronic administration of JWH-133. Ovarian cancer tumor tissues chronically (30\u00a0days) treated with JWH-133 in comparison to vehicle treated groups showed an increase in endocannabinoid (AEA and 2-AG) and protein (CB<jats:sub>2<\/jats:sub> and TNF\u03b1) levels with a decrease in GPER protein levels. Interestingly, our study emphasizes the importance of studying the impact of cannabinoid compounds on already established tumors to improve our understanding of cannabinoid-based therapies and, therefore better address clinical needs in cancer patients.<\/jats:p>","DOI":"10.3389\/fphar.2022.823132","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T07:51:31Z","timestamp":1644911491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Chronic Administration of Cannabinoid Receptor 2 Agonist (JWH-133) Increases Ectopic Ovarian Tumor Growth and Endocannabinoids (Anandamide and 2-Arachidonoyl Glycerol) Levels in Immunocompromised SCID Female Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Henry L.","family":"Blanton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa C.","family":"McHann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"De Selle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canice Lei","family":"Dancel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose-Luis","family":"Redondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Molehin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezhda A.","family":"German","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Trasti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Pruitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Castro-Piedras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9e","family":"Guindon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2881","DOI":"10.2174\/1381612827666210426092847","article-title":"The Molecular Targets of Cannabinoids in the Treatment of Cancer and Inflammation","volume":"27","author":"Aylar","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"B2","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00280-017-3387-5","article-title":"A Review of Oral Cannabinoids and Medical Marijuana for the Treatment of Chemotherapy-Induced Nausea and Vomiting: a Focus on Pharmacokinetic Variability and Pharmacodynamics","volume":"80","author":"Badowski","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"S215","DOI":"10.21037\/apm.2017.08.05","article-title":"A Selective Review of Medical Cannabis in Cancer Pain Management","volume":"6","author":"Blake","year":"2017","journal-title":"Ann. Palliat. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.chembiol.2007.11.006","article-title":"A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2-arachidonoylglycerol","volume":"14","author":"Blankman","year":"2007","journal-title":"Chem. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1007\/s40265-019-01132-x","article-title":"Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain","volume":"79","author":"Blanton","year":"2019","journal-title":"Drugs"},{"key":"B6","volume-title":"Cannabis: A History","author":"Booth","year":"2003"},{"key":"B7","doi-asserted-by":"publisher","first-page":"R349","DOI":"10.1152\/ajpregu.00933.2005","article-title":"Sex and Hormonal Cycle Differences in Rat Brain Levels of Pain-Related Cannabimimetic Lipid Mediators","volume":"291","author":"Bradshaw","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1016\/j.annonc.2020.09.010","article-title":"5th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 5)","volume":"31","author":"Cardoso","year":"2020","journal-title":"Ann. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e50600","DOI":"10.15252\/embr.202050600","article-title":"Nuclear Dishevelled Targets Gene Regulatory Regions and Promotes Tumor Growth","volume":"22","author":"Castro-Piedras","year":"2021","journal-title":"EMBO Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/384083a0","article-title":"Molecular Characterization of an Enzyme that Degrades Neuromodulatory Fatty-Acid Amides","volume":"384","author":"Cravatt","year":"1996","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2147\/JPR.S160556","article-title":"Pharmacotherapeutic Considerations for Use of Cannabinoids to Relieve Pain in Patients with Malignant Diseases","volume":"11","author":"Darkovska-Serafimovska","year":"2018","journal-title":"J. Pain Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.apsb.2019.10.006","article-title":"Monoacylglycerol Lipase Inhibitors: Modulators for Lipid Metabolism in Cancer Malignancy, Neurological and Metabolic Disorders","volume":"10","author":"Deng","year":"2020","journal-title":"Acta Pharm. Sin B"},{"key":"B13","first-page":"605","article-title":"Determination and Characterization of a Cannabinoid Receptor in Rat Brain","volume":"34","author":"Devane","year":"1988","journal-title":"Mol. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1126\/science.1470919","article-title":"Isolation and Structure of a Brain Constituent that Binds to the Cannabinoid Receptor","volume":"258","author":"Devane","year":"1992","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"10819","DOI":"10.1073\/pnas.152334899","article-title":"Brain Monoglyceride Lipase Participating in Endocannabinoid Inactivation","volume":"99","author":"Dinh","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B16","doi-asserted-by":"publisher","first-page":"29668","DOI":"10.18632\/oncotarget.9408","article-title":"Novel Role of Cannabinoid Receptor 2 in Inhibiting EGF\/EGFR and IGF-I\/IGF-IR Pathways in Breast Cancer","volume":"8","author":"Elbaz","year":"2017","journal-title":"Oncotarget"},{"key":"B17","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/s0006-2952(98)00314-1","article-title":"Enzymes of Porcine Brain Hydrolyzing 2-arachidonoylglycerol, an Endogenous Ligand of Cannabinoid Receptors","volume":"57","author":"Goparaju","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1111\/j.1476-5381.2010.01192.x","article-title":"Peripheral Antinociceptive Effects of Inhibitors of Monoacylglycerol Lipase in a Rat Model of Inflammatory Pain","volume":"163","author":"Guindon","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1111\/j.1476-5381.2011.01327.x","article-title":"The Endocannabinoid System and Cancer: Therapeutic Implication","volume":"163","author":"Guindon","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.phrs.2012.10.013","article-title":"Alterations in Endocannabinoid Tone Following Chemotherapy-Induced Peripheral Neuropathy: Effects of Endocannabinoid Deactivation Inhibitors Targeting Fatty-Acid Amide Hydrolase and Monoacylglycerol Lipase in Comparison to Reference Analgesics Following Cisplatin Treatment","volume":"67","author":"Guindon","year":"2013","journal-title":"Pharmacol. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/sj.bjc.6603236","article-title":"A Pilot Clinical Study of Delta9-tetrahydrocannabinol in Patients with Recurrent Glioblastoma Multiforme","volume":"95","author":"Guzm\u00e1n","year":"2006","journal-title":"Br. J. Cancer"},{"key":"B22","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1021\/ja01062a046","article-title":"Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish","volume":"86","author":"Gaoni","year":"1964","journal-title":"J. Am. Chem. Soc."},{"key":"B23","doi-asserted-by":"publisher","first-page":"59","DOI":"10.2147\/BCTT.S100393","article-title":"Modulation of Breast Cancer Cell Viability by a Cannabinoid Receptor 2 Agonist, JWH-015, Is Calcium Dependent","volume":"8","author":"Hanlon","year":"2016","journal-title":"Breast Cancer (Dove Med. Press."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1111\/bph.14426","article-title":"Anti-tumour Actions of Cannabinoids","volume":"176","author":"Hinz","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.3390\/cancers13051064","article-title":"THC Reduces Ki67-Immunoreactive Cells Derived from Human Primary Glioblastoma in a GPR55-dependent Manner","volume":"13","author":"Kolbe","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3322\/caac.21260","article-title":"Medical Marijuana for Cancer","volume":"65","author":"Kramer","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"B27","doi-asserted-by":"publisher","first-page":"361","DOI":"10.3389\/fphar.2016.00361","article-title":"Preclinical and Clinical Assessment of Cannabinoids as Anti-cancer Agents","volume":"7","author":"Ladin","year":"2016","journal-title":"Front. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.3892\/mmr.2014.2914","article-title":"Ki67 Is a Promising Molecular Target in the Diagnosis of Cancer (Review)","volume":"11","author":"Li","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1002\/jbmr.1732","article-title":"Disease Modification of Breast Cancer-Induced Bone Remodeling by Cannabinoid 2 Receptor Agonists","volume":"28","author":"Lozano-Ondoua","year":"2013","journal-title":"J. Bone Miner Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ejphar.2009.06.004","article-title":"The CB1\/CB2 Receptor Agonist WIN-55,212-2 Reduces Viability of Human Kaposi's Sarcoma Cells In Vitro","volume":"616","author":"Luca","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ejim.2018.01.004","article-title":"Practical Considerations in Medical Cannabis Administration and Dosing","volume":"49","author":"MacCallum","year":"2018","journal-title":"Eur. J. Intern. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"398","DOI":"10.3747\/co.23.3487","article-title":"A User's Guide to Cannabinoid Therapies in Oncology","volume":"23","author":"Maida","year":"2016","journal-title":"Curr. Oncol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/nrc.2017.69","article-title":"Classifying the Evolutionary and Ecological Features of Neoplasms","volume":"17","author":"Maley","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1158\/1535-7163.MCT-09-0407","article-title":"Cannabidiol Enhances the Inhibitory Effects of delta9-tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival","volume":"9","author":"Marcu","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"B35","doi-asserted-by":"publisher","first-page":"68781","DOI":"10.18632\/oncotarget.11968","article-title":"CB2 Cannabinoid Receptor Activation Promotes colon Cancer Progression via AKT\/GSK3\u03b2 Signaling Pathway","volume":"7","author":"Mart\u00ednez-Mart\u00ednez","year":"2016","journal-title":"Oncotarget"},{"key":"B36","volume-title":"General Techniques of Cell Culture","author":"Maureen","year":"1997"},{"key":"B37","doi-asserted-by":"publisher","first-page":"111320","DOI":"10.1016\/j.mce.2021.111320","article-title":"Role of Sex Hormones in Modulating Breast and Ovarian Cancer Associated Pain","volume":"533","author":"McHann","year":"2021","journal-title":"Mol. Cel Endocrinol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1300\/j175v01n03_08","article-title":"Cannabis and Cannabis Extracts","volume":"1","author":"McPartland","year":"2001","journal-title":"J. Cannabis Ther."},{"key":"B39","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/0006-2952(95)00109-d","article-title":"Identification of an Endogenous 2-monoglyceride, Present in Canine Gut, that Binds to Cannabinoid Receptors","volume":"50","author":"Mechoulam","year":"1995","journal-title":"Biochem. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.3390\/cancers12113275","article-title":"The Interplay between Cancer Biology and the Endocannabinoid System-Significance for Cancer Risk, Prognosis and Response to Treatment","volume":"12","author":"Moreno","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/365061a0","article-title":"Molecular Characterization of a Peripheral Receptor for Cannabinoids","volume":"365","author":"Munro","year":"1993","journal-title":"Nature"},{"key":"B42","volume-title":"Guide for the Care and Use of Laboratory Animals: Eighth Edition 2011","year":"2011"},{"key":"B43","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cell.2009.11.027","article-title":"Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis","volume":"140","author":"Nomura","year":"2010","journal-title":"Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1111\/j.1476-5381.2010.01176.x","article-title":"Regulation of Nausea and Vomiting by Cannabinoids","volume":"163","author":"Parker","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/sj.bjp.0707442","article-title":"The Diverse CB1 and CB2 Receptor Pharmacology of Three Plant Cannabinoids: delta9-tetrahydrocannabinol, Cannabidiol and delta9-tetrahydrocannabivarin","volume":"153","author":"Pertwee","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.canlet.2011.07.008","article-title":"The Antimitogenic Effect of the Cannabinoid Receptor Agonist WIN55212-2 on Human Melanoma Cells Is Mediated by the Membrane Lipid Raft","volume":"310","author":"Scuderi","year":"2011","journal-title":"Cancer Lett."},{"key":"B47","first-page":"989","article-title":"Evaluation of Binding in a Transfected Cell Line Expressing a Peripheral Cannabinoid Receptor (CB2): Identification of Cannabinoid Receptor Subtype Selective Ligands","volume":"278","author":"Showalter","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B48","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.pdpdt.2018.09.006","article-title":"Combined CB2 Receptor Agonist and Photodynamic Therapy Synergistically Inhibit Tumor Growth in Triple Negative Breast Cancer","volume":"24","author":"Zhang","year":"2018","journal-title":"Photodiagnosis Photodyn Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.823132\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T07:51:39Z","timestamp":1644911499000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.823132\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,15]]},"references-count":48,"alternative-id":["10.3389\/fphar.2022.823132"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.823132","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,15]]},"article-number":"823132"}}