{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:07:33Z","timestamp":1774379253246,"version":"3.50.1"},"reference-count":40,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>The dopamine agonist cabergoline (CAB) has been used widely in the treatment of prolactinomas and other types of pituitary adenomas, but its clinical use is hampered by intolerance in some patients with prolactinoma and lack of effectiveness in other pituitary tumor types. Chloroquine (CQ) is an old drug widely used to treat malaria. Recent studies, including our own, have revealed that CAB and CQ are involved in induction of autophagy and activation of autophagic cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To test whether CAB and CQ can function cooperatively to suppress growth of pituitary adenomas as well as other cancers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vitro studies using the rat pituitary tumor cell lines MMQ and GH3, human pituitary tumor cell primary cultures, and several human cancer cell lines showed that CQ enhanced suppression of cell proliferation by CAB. These results were confirmed in in vivo xenograft models in nude mice and estrogen-induced rat prolactinomas. To understand the mechanism of combined CAB and CQ action, we established a low-CAB-dose condition in which CAB was able to induce autophagy but failed to suppress cell growth. Addition of CQ to low-dose CAB blocked normal autophagic cycles and induced apoptosis, evidenced by the further accumulation of p62\/caspase-8\/LC3-II.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The data suggest that combined use of CAB and CQ may increase clinical effectiveness in treatment of human pituitary adenomas, as well as other cancers, making it an attractive option in tumor and cancer therapies.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2017-00627","type":"journal-article","created":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T18:03:49Z","timestamp":1500573829000},"page":"3692-3703","source":"Crossref","is-referenced-by-count":35,"title":["Pituitary Tumor Suppression by Combination of Cabergoline and Chloroquine"],"prefix":"10.1210","volume":"102","author":[{"given":"Shao Jian","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu Hang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han Bing","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei Guo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Neuroendocrine Research Laboratory, Massachusetts General Hospital and Harvard Medical School, 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Endocrinol"},{"issue":"5","key":"2020071619460288600_B3","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1210\/er.2005-9998","article-title":"Advances in the treatment of prolactinomas","volume":"27","author":"Gillam","year":"2006","journal-title":"Endocr Rev"},{"issue":"5","key":"2020071619460288600_B4","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1111\/cen.12684","article-title":"Dopamine receptor subtype 2 expression profile in nonfunctioning pituitary adenomas and in vivo response to cabergoline therapy","volume":"82","author":"Vieira Neto","year":"2015","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"4","key":"2020071619460288600_B5","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1507\/endocrj.EJ12-0272","article-title":"Efficacy of combined octreotide and cabergoline treatment in patients with acromegaly: a retrospective clinical study and review of the literature","volume":"60","author":"Suda","year":"2013","journal-title":"Endocr J"},{"issue":"19","key":"2020071619460288600_B6","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1056\/NEJMc1000094","article-title":"Pasireotide alone or with cabergoline and ketoconazole in Cushing\u2019s disease","volume":"362","author":"Feelders","year":"2010","journal-title":"N Engl J Med"},{"issue":"36","key":"2020071619460288600_B7","doi-asserted-by":"crossref","first-page":"39329","DOI":"10.18632\/oncotarget.5744","article-title":"Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline","volume":"6","author":"Lin","year":"2015","journal-title":"Oncotarget"},{"issue":"1-3","key":"2020071619460288600_B8","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ejphar.2009.06.063","article-title":"Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies","volume":"625","author":"Solomon","year":"2009","journal-title":"Eur J Pharmacol"},{"issue":"6246","key":"2020071619460288600_B9","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1126\/science.aaa1663","article-title":"AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy","volume":"349","author":"Lo","year":"2015","journal-title":"Science"},{"key":"2020071619460288600_B10","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3389\/fimmu.2016.00350","article-title":"Endogenous n-3 polyunsaturated fatty acids attenuate T cell-mediated hepatitis via autophagy activation","volume":"7","author":"Li","year":"2016","journal-title":"Front Immunol"},{"issue":"8","key":"2020071619460288600_B11","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.4161\/auto.29231","article-title":"Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors","volume":"10","author":"Mahalingam","year":"2014","journal-title":"Autophagy"},{"issue":"10","key":"2020071619460288600_B12","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1097\/JTO.0b013e318262de4a","article-title":"A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer","volume":"7","author":"Goldberg","year":"2012","journal-title":"J Thorac Oncol"},{"key":"2020071619460288600_B13","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1186\/1471-2407-10-370","article-title":"Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells","volume":"10","author":"Sasaki","year":"2010","journal-title":"BMC Cancer"},{"issue":"5","key":"2020071619460288600_B14","doi-asserted-by":"crossref","first-page":"337","DOI":"10.7326\/0003-4819-144-5-200603070-00008","article-title":"Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled 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breast cancers","volume":"10","author":"Lefort","year":"2014","journal-title":"Autophagy"},{"issue":"6","key":"2020071619460288600_B18","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1634\/theoncologist.2014-0086","article-title":"Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma","volume":"19","author":"Wolpin","year":"2014","journal-title":"Oncologist"},{"issue":"8","key":"2020071619460288600_B19","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.4161\/auto.28984","article-title":"A phase I\/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme","volume":"10","author":"Rosenfeld","year":"2014","journal-title":"Autophagy"},{"issue":"9","key":"2020071619460288600_B20","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrd3802","article-title":"Autophagy modulation as a potential therapeutic target for diverse diseases","volume":"11","author":"Rubinsztein","year":"2012","journal-title":"Nat Rev Drug Discov"},{"issue":"10","key":"2020071619460288600_B21","doi-asserted-by":"crossref","first-page":"e74596","DOI":"10.1371\/journal.pone.0074596","article-title":"Characterization of the mechanism of inhibin \u03b1-subunit gene in mouse anterior pituitary cells by RNA interference","volume":"8","author":"Han","year":"2013","journal-title":"PLoS One"},{"issue":"9","key":"2020071619460288600_B22","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/neuonc\/not078","article-title":"High-mobility group box 2 is associated with prognosis of glioblastoma by promoting cell viability, invasion, and chemotherapeutic resistance","volume":"15","author":"Wu","year":"2013","journal-title":"Neuro-oncol"},{"issue":"3","key":"2020071619460288600_B23","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/BF00300234","article-title":"Determination of subcutaneous tumor size in athymic (nude) mice","volume":"24","author":"Tomayko","year":"1989","journal-title":"Cancer Chemother Pharmacol"},{"issue":"3","key":"2020071619460288600_B24","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s11060-013-1351-8","article-title":"Effects of the estrogen receptor antagonist fulvestrant on F344 rat prolactinoma models","volume":"116","author":"Cao","year":"2014","journal-title":"J Neurooncol"},{"issue":"1","key":"2020071619460288600_B25","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1750-3639.2011.00544.x","article-title":"Autophagy in brain tumors: a new target for therapeutic intervention","volume":"22","author":"Kaza","year":"2012","journal-title":"Brain Pathol"},{"issue":"15","key":"2020071619460288600_B26","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1074\/jbc.M111.309104","article-title":"Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis","volume":"287","author":"Young","year":"2012","journal-title":"J Biol Chem"},{"issue":"47","key":"2020071619460288600_B27","doi-asserted-by":"crossref","first-page":"33654","DOI":"10.1074\/jbc.M113.518134","article-title":"p62\/sequestosome-1 up-regulation promotes ABT-263-induced caspase-8 aggregation\/activation on the autophagosome","volume":"288","author":"Huang","year":"2013","journal-title":"J Biol Chem"},{"issue":"24","key":"2020071619460288600_B28","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1038\/onc.2015.369","article-title":"Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer","volume":"35","author":"Borcherding","year":"2016","journal-title":"Oncogene"},{"issue":"3","key":"2020071619460288600_B29","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1159\/000381061","article-title":"Expression of somatostatin receptors 1-5 and dopamine receptor 2 in lung carcinoids: implications for a therapeutic role","volume":"101","author":"Kanakis","year":"2015","journal-title":"Neuroendocrinology"},{"issue":"6","key":"2020071619460288600_B30","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.2353\/ajpath.2010.100617","article-title":"Dopamine, by acting through its D2 receptor, inhibits insulin-like growth factor-I (IGF-I)-induced gastric cancer cell proliferation via up-regulation of Kr\u00fcppel-like factor 4 through down-regulation of IGF-IR and AKT phosphorylation","volume":"177","author":"Ganguly","year":"2010","journal-title":"Am J Pathol"},{"issue":"5","key":"2020071619460288600_B31","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1016\/j.fertnstert.2014.07.1240","article-title":"Dopamine receptor 2 activation inhibits ovarian vascular endothelial growth factor secretion in an ovarian hyperstimulation syndrome (OHSS) animal model: implications for treatment of OHSS with dopamine receptor 2 agonists","volume":"102","author":"Ferrero","year":"2014","journal-title":"Fertil Steril"},{"key":"2020071619460288600_B32","first-page":"1543","article-title":"Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis","volume":"8","author":"Lu","year":"2015","journal-title":"Onco Targets Ther"},{"issue":"9","key":"2020071619460288600_B33","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1007\/s00268-006-0035-3","article-title":"DRD2\/DARPP-32 expression correlates with lymph node metastasis and tumor progression in patients with esophageal squamous cell carcinoma","volume":"30","author":"Li","year":"2006","journal-title":"World J Surg"},{"key":"2020071619460288600_B34","doi-asserted-by":"crossref","unstructured":"Leng ZG , LinSJ, WuZR, GuoYH, CaiL, ShangHB, TangH, XueYJ, LouMQ, ZhaoW, LeW-D, ZhaoWG, ZhangX, WuZB. Activation of DRD5 (dopamine receptor d5) inhibits tumor growth by autophagic cell death [published online ahead of print June 14, 2017]. Autophagy. doi:10.1080\/15548627.2017.1328347.","DOI":"10.1080\/15548627.2017.1328347"},{"issue":"33","key":"2020071619460288600_B35","doi-asserted-by":"crossref","first-page":"24131","DOI":"10.1074\/jbc.M702824200","article-title":"p62\/SQSTM1 binds directly to Atg8\/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy","volume":"282","author":"Pankiv","year":"2007","journal-title":"J Biol Chem"},{"issue":"4","key":"2020071619460288600_B36","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.cell.2009.03.015","article-title":"Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling","volume":"137","author":"Jin","year":"2009","journal-title":"Cell"},{"issue":"10","key":"2020071619460288600_B37","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1210\/jc.2002-020426","article-title":"The novel use of very high doses of cabergoline and a combination of testosterone and an aromatase inhibitor in the treatment of a giant prolactinoma","volume":"87","author":"Gillam","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2020071619460288600_B38","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1210\/jc.2007-2758","article-title":"Prospective study of high-dose cabergoline treatment of prolactinomas in 150 patients","volume":"93","author":"Ono","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2020071619460288600_B39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1158\/0008-5472.CAN-12-2464","article-title":"Chloroquine in cancer therapy: a double-edged sword of autophagy","volume":"73","author":"Kimura","year":"2013","journal-title":"Cancer Res"},{"issue":"4","key":"2020071619460288600_B40","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1158\/1078-0432.CCR-10-2634","article-title":"Principles and current strategies for targeting autophagy for cancer treatment","volume":"17","author":"Amaravadi","year":"2011","journal-title":"Clin Cancer Res"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/102\/10\/3692\/20619951\/jc.2017-00627.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/102\/10\/3692\/20619951\/jc.2017-00627.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T07:08:59Z","timestamp":1659251339000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/102\/10\/3692\/3979819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,20]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2017,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2017-00627","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,10,1]]},"published":{"date-parts":[[2017,7,20]]}}}