{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T02:48:23Z","timestamp":1793760503666,"version":"4.6.1"},"reference-count":63,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Environmental Health Sciences","award":["ZIA E505013922"],"award-info":[{"award-number":["ZIA E505013922"]}]},{"name":"National Institute of Environmental Health Sciences","award":["CARCI-HEI #"],"award-info":[{"award-number":["CARCI-HEI #"]}]},{"name":"National Institute of Environmental Health Sciences","award":["ZIA ES103383-01"],"award-info":[{"award-number":["ZIA ES103383-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Erastin (ER) induces cell death through the formation of reactive oxygen species (ROS), resulting in ferroptosis. Ferroptosis is characterized by an accumulation of ROS within the cell, leading to an iron-dependent oxidative damage-mediated cell death. ER-induced ferroptosis may have potential as an alternative for ovarian cancers that have become resistant due to the presence of Ras mutation or multi-drug resistance1 (MDR1) gene expression. We used K-Ras mutant human ovarian tumor OVCAR-8 and NCI\/ADR-RES, P-glycoprotein-expressing cells, to study the mechanisms of ER-induced cell death. We used these cell lines as NCI\/ADR-RES cells also overexpresses superoxide dismutase, catalase, glutathione peroxidase, and transferase compared to OVCAR-8 cells, leading to the detoxification of reactive oxygen species. We found that ER was similarly cytotoxic to both cells. Ferrostatin, an inhibitor of ferroptosis, reduced ER cytotoxicity. In contrast, RSL3 (RAS-Selective Ligand3), an inducer of ferroptosis, markedly enhanced ER cytotoxicity in both cells. More ROS was detected in OVCAR-8 cells than NCI\/ADR-RES cells, causing more malondialdehyde (MDA) formation in OVCAR-8 cells than in NCI\/ADR-RES cells. RSL3, which was more cytotoxic to NCI\/ADR-RES cells, significantly enhanced MDA formation in both cells, suggesting that glutathione peroxidase 4 (GPX4) was involved in ER-mediated ferroptosis. ER treatment modulated several ferroptosis-related genes (e.g., CHAC1, GSR, and HMOX1\/OX1) in both cells. Our study indicates that ER-induced ferroptotic cell death may be mediated similarly in both NCI\/ADR-RES and OVCAR-8 cells. Additionally, our results indicate that ER is not a substrate of P-gp and that combinations of ER and RSL3 may hold promise as more effective treatment routes for ovarian cancers, including those that are resistant to other current therapeutic agents.<\/jats:p>","DOI":"10.3390\/ijms25168666","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T15:04:24Z","timestamp":1723129464000},"page":"8666","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mechanisms of Cell Death Induced by Erastin in Human Ovarian Tumor Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Birandra K.","family":"Sinha","sequence":"first","affiliation":[{"name":"Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health, NIH, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carri","family":"Murphy","sequence":"additional","affiliation":[{"name":"Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health, NIH, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalyn M.","family":"Brown","sequence":"additional","affiliation":[{"name":"Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health, NIH, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian B.","family":"Silver","sequence":"additional","affiliation":[{"name":"Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health, NIH, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1668-2830","authenticated-orcid":false,"given":"Erik J.","family":"Tokar","sequence":"additional","affiliation":[{"name":"Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health, NIH, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-6628","authenticated-orcid":false,"given":"Carl D.","family":"Bortner","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction, National Institutes of Environmental Health, NIH, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.soncn.2019.02.001","article-title":"Ovarian Cancer: An Integrated Review","volume":"35","author":"Stewart","year":"2019","journal-title":"Semin. 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