{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:49Z","timestamp":1787027809550,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007397","name":"Charles University institutional research fund","doi-asserted-by":"publisher","award":["SVV-260571\/2020"],"award-info":[{"award-number":["SVV-260571\/2020"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University institutional research fund","doi-asserted-by":"publisher","award":["1722218"],"award-info":[{"award-number":["1722218"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University institutional research fund","doi-asserted-by":"publisher","award":["CZ.1.05\/4.1.00\/16.0347"],"award-info":[{"award-number":["CZ.1.05\/4.1.00\/16.0347"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["SVV-260571\/2020"],"award-info":[{"award-number":["SVV-260571\/2020"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["1722218"],"award-info":[{"award-number":["1722218"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["CZ.1.05\/4.1.00\/16.0347"],"award-info":[{"award-number":["CZ.1.05\/4.1.00\/16.0347"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Regional Development Fund and the state budget of the Czech Republic","award":["SVV-260571\/2020"],"award-info":[{"award-number":["SVV-260571\/2020"]}]},{"name":"European Regional Development Fund and the state budget of the Czech Republic","award":["1722218"],"award-info":[{"award-number":["1722218"]}]},{"name":"European Regional Development Fund and the state budget of the Czech Republic","award":["CZ.1.05\/4.1.00\/16.0347"],"award-info":[{"award-number":["CZ.1.05\/4.1.00\/16.0347"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Methadone is commonly used as an alternative to morphine in patients with pain associated with glioblastoma and other cancers. Although concomitant administration of methadone and cytostatics is relatively common, the effect of methadone on the efficacy of cytostatic drugs has not been well studied until recently. Moreover, the mechanism behind the effect of methadone on temozolomide efficacy has not been investigated in previous studies, or this effect has been automatically attributed to opioid receptors. Our findings indicate that methadone potentiates the effect of temozolomide on rat C6 glioblastoma cells and on human U251 and T98G glioblastoma cells and increases cell mortality by approximately 50% via a mechanism of action independent of opioid receptors. Our data suggest that methadone acts by affecting mitochondrial potential, the level of oxidative stress, intracellular Ca2+ concentration and possibly intracellular ATP levels. Significant effects were also observed on DNA integrity and on cleavage and expression of the DNA repair protein PARP-1. None of these effects were attributed to the activation of opioid receptors and Toll-like receptor 4. Our results provide an alternative perspective on the mechanism of action of methadone in combination with temozolomide and a potential strategy for the treatment of glioblastoma cell resistance to temozolomide.<\/jats:p>","DOI":"10.3390\/cancers15143567","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T01:01:41Z","timestamp":1689123701000},"page":"3567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Methadone Potentiates the Cytotoxicity of Temozolomide by Impairing Calcium Homeostasis and Dysregulation of PARP in Glioblastoma Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0727-7956","authenticated-orcid":false,"given":"Ondrej","family":"Honc","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6372-0131","authenticated-orcid":false,"given":"Jiri","family":"Novotny","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.neo.2014.08.015","article-title":"Therapeutic Efficacy of Aldoxorubicin in an Intracranial Xenograft Mouse Model of Human Glioblastoma","volume":"16","author":"Marrero","year":"2014","journal-title":"Neoplasia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"935","DOI":"10.3892\/mco.2013.172","article-title":"Glioma and Glioblastoma-How Much Do We (Not) Know?","volume":"1","author":"Komel","year":"2013","journal-title":"Mol. 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