{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T19:27:38Z","timestamp":1783970858987,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016047","name":"Science Fund of the Republic of Serbia","doi-asserted-by":"publisher","award":["7005"],"award-info":[{"award-number":["7005"]}],"id":[{"id":"10.13039\/501100016047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Multidrug resistance (MDR) presents a significant challenge in the treatment of glioblastoma. We evaluated six novel adamantane\u2013sclareol hybrids that integrate a natural labdane diterpene scaffold with an adamantane moiety to address this issue. Compounds 2, 5, and 6 demonstrated the ability to bypass P-glycoprotein (P-gp)-mediated resistance in resistant U87-TxR cells and induced collateral sensitivity, with compound 2 exhibiting the highest selectivity for glioblastoma compared to normal glial cells. Mechanistic studies revealed that compounds 2 and 5 selectively triggered early apoptosis in MDR cells, significantly elevated levels of H2O2 and peroxynitrite, and disrupted mitochondrial membrane potential. Additionally, these compounds altered the expression of key genes involved in glutathione (GSH) and thioredoxin (Trx) antioxidant defense systems and increased ASK1 protein levels, indicating the activation of ROS-driven apoptotic signaling. Both compounds inhibited P-gp function, leading to enhanced intracellular accumulation of rhodamine 123 (Rho 123) and synergistically sensitized U87-TxR cells to paclitaxel (PTX). A preliminary Rag1 xenograft study demonstrated that compound 5 effectively suppressed tumor growth without causing significant weight loss. Collectively, these findings position adamantane\u2013sclareol hybrids, particularly compounds 2 and 5, as promising strategies that exploit an MDR-associated reactive oxygen species (ROS) vulnerability, combining selective cytotoxicity, redox disruption, and P-gp modulation to eliminate resistant glioblastoma cells and enhance the efficacy of chemotherapeutics.<\/jats:p>","DOI":"10.3390\/molecules30244756","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T11:13:33Z","timestamp":1765538013000},"page":"4756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel Adamantane\u2013Sclareol Hybrids Exploit ROS Vulnerability to Overcome Multidrug-Resistance in Glioblastoma Cells"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-1689","authenticated-orcid":false,"given":"Ema","family":"Lup\u0161i\u0107","sequence":"first","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2013National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4660-5537","authenticated-orcid":false,"given":"Pavle","family":"Stojkovi\u0107","sequence":"additional","affiliation":[{"name":"University of Belgrade\u2013Faculty of Chemistry, P.O. Box 51, Studentski Trg 16, 11158 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7425-685X","authenticated-orcid":false,"given":"Marija","family":"Grozdani\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2013National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4127-525X","authenticated-orcid":false,"given":"Nata\u0161a","family":"Terzi\u0107-Jovanovi\u0107","sequence":"additional","affiliation":[{"name":"University of Belgrade\u2013Institute of Chemistry, Technology, and Metallurgy, National Institute of the Republic of Serbia, Njego\u0161eva 12, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-0861","authenticated-orcid":false,"given":"Milica","family":"Pajovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2013National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fani","family":"Koutsougianni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Panepistimiou 3 (Biopolis), 41500 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Alexopoulou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Panepistimiou 3 (Biopolis), 41500 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor M.","family":"Opsenica","sequence":"additional","affiliation":[{"name":"University of Belgrade\u2013Faculty of Chemistry, P.O. Box 51, Studentski Trg 16, 11158 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9045-8239","authenticated-orcid":false,"given":"Milica","family":"Pe\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2013National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7412-3685","authenticated-orcid":false,"given":"Ana","family":"Podolski-Reni\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2013National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","first-page":"299","article-title":"Management of Glioblastoma: State of the Art and Future Directions","volume":"70","author":"Tan","year":"2020","journal-title":"CA A Cancer J. 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