{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T17:23:13Z","timestamp":1782321793202,"version":"3.54.5"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011597","name":"Penn State Hershey Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011597","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32CA060395\u201021A1"],"award-info":[{"award-number":["T32CA060395\u201021A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dopamine D<jats:sub>2<\/jats:sub>\u2010like receptor antagonists have been suggested as being potential anticancer therapeutics with specific utility for central nervous system cancers due to their ability to cross the blood\u2010brain barrier. Despite a plethora of data reporting anticancer effects for D<jats:sub>2<\/jats:sub>R antagonists in cell or animal studies, the ligand concentrations or doses required to achieve such effects greatly exceed the levels known to cause high degrees of occupancy of the D<jats:sub>2<\/jats:sub> receptor. To resolve this conundrum, we interrogated a panel of glioblastoma multiforme (GBM) cell lines using D<jats:sub>2<\/jats:sub> antagonists of varying chemotype. We studied the cytotoxic effects of these compounds, and also ascertained the expression of D<jats:sub>2<\/jats:sub> receptors (D<jats:sub>2<\/jats:sub>R) on these cells. Although several chemotypes of D<jats:sub>2<\/jats:sub>R antagonists, including phenothiazines and phenylbutylpiperidines, were effective against GBM cell line cultures, the highly selective antagonist remoxipride had no anticancer activity at biologically relevant concentrations. Moreover the D<jats:sub>2<\/jats:sub>R antagonist\u2010induced cytotoxicity in monolayer cultures was independent of whether the cells expressed D<jats:sub>2<\/jats:sub>R. Instead, cytotoxicity was associated with a rapid, high\u2010magnitude calcium flux into the cytoplasm and mitochondria, which then induced depolarization and apoptosis. Blocking this flux protected the GBM cell lines U87MG, U251MG, and A172. Together, these data suggest that the cytotoxicity of these D<jats:sub>2<\/jats:sub>R antagonists involves calcium signaling mechanisms, not D<jats:sub>2<\/jats:sub>R antagonism. Repurposing of existing drugs should focus on the former, not latter, mechanism.<\/jats:p>","DOI":"10.1002\/prp2.689","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T14:14:41Z","timestamp":1621347281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium\u2010dependent, non\u2010D<sub>2<\/sub> receptor\u2010dependent, manner"],"prefix":"10.1002","volume":"9","author":[{"given":"Jillian S.","family":"Weissenrieder","sequence":"first","affiliation":[{"name":"Department of Medicine Penn State College of Medicine Hershey PA USA"},{"name":"Department of Pharmacology Penn State College of Medicine Hershey PA USA"},{"name":"Penn State Cancer Institute Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie L.","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Medicine Penn State College of Medicine Hershey PA USA"},{"name":"Department of Pharmacology Penn State College of Medicine Hershey PA USA"},{"name":"Penn State Cancer Institute Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George\u2010Lucian","family":"Moldovan","sequence":"additional","affiliation":[{"name":"Penn State Cancer Institute Hershey PA USA"},{"name":"Department of Biochemistry and Molecular Biology Penn State College of Medicine Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin T.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Penn State Cancer Institute Hershey PA USA"},{"name":"Department of Cellular and Molecular Physiology Penn State College of Medicine Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Trebak","sequence":"additional","affiliation":[{"name":"Penn State Cancer Institute Hershey PA USA"},{"name":"Department of Cellular and Molecular Physiology Penn State College of Medicine Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0698-4181","authenticated-orcid":false,"given":"Jeffrey D.","family":"Neighbors","sequence":"additional","affiliation":[{"name":"Department of Medicine Penn State College of Medicine Hershey PA USA"},{"name":"Department of Pharmacology Penn State College of Medicine Hershey PA USA"},{"name":"Penn State Cancer Institute Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Mailman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Penn State College of Medicine Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond J.","family":"Hohl","sequence":"additional","affiliation":[{"name":"Department of Medicine Penn State College of Medicine Hershey PA USA"},{"name":"Department of Pharmacology Penn State College of Medicine Hershey PA USA"},{"name":"Penn State Cancer Institute Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00462"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12785"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-25761-2_3"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.08.040"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1801"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.05.002"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2217\/rme.12.60"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1233"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11691"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.256818"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e03-05-0293"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401263"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.23707"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)83641-4"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5153"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"issue":"1","key":"e_1_2_10_18_1","first-page":"S21","article-title":"THE CONCISE GUIDE TO PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander SPH","year":"2019","journal-title":"Br J Pharmacol"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.09.024"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.02.030"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.18"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.141.3.352"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2014.3068"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.11.002"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9881"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0720479.x"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.214411"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00222"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.03.014"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2017.10.002"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1159\/000502562"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.084202"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.689","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.689","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.689","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T06:46:43Z","timestamp":1693205203000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":31,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1002\/prp2.689"],"URL":"https:\/\/doi.org\/10.1002\/prp2.689","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]},"assertion":[{"value":"2020-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00689"}}