{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:27:50Z","timestamp":1788402470548,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education (MOHE) Malaysia","doi-asserted-by":"crossref","award":["FRGS\/1\/2022\/STG01\/UNIKL\/02\/3"],"award-info":[{"award-number":["FRGS\/1\/2022\/STG01\/UNIKL\/02\/3"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC50-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting.<\/jats:p>","DOI":"10.3390\/antiox15030288","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T10:33:02Z","timestamp":1772101982000},"page":"288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Curcumin Synergistically Sensitizes Multidrug-Resistant Lung Cancer to Doxorubicin Through Ferroptosis-Associated Oxidative Stress"],"prefix":"10.3390","volume":"15","author":[{"given":"Wing-Hin","family":"Lee","sequence":"first","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL RCMP), Ipoh 30450, Perak, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9982-7347","authenticated-orcid":false,"given":"Ching-Yee","family":"Loo","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL RCMP), Ipoh 30450, Perak, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poh Yen","family":"Khor","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL RCMP), Ipoh 30450, Perak, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9644-6688","authenticated-orcid":false,"given":"Charles","family":"Gnanaraj","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL RCMP), Ipoh 30450, Perak, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai Ping","family":"Koh","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Quest International University, Ipoh 30250, Perak, Malaysia"},{"name":"Centre for Stem Cell Research, Quest International University, Ipoh 30250, Perak, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chean Ring","family":"Leong","sequence":"additional","affiliation":[{"name":"Malaysian Institute of Chemical and Bioengineering Technology, Universiti Kuala Lumpur, Alor Gajah 78000, Melaka, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7507-1159","authenticated-orcid":false,"given":"Kamal","family":"Dua","sequence":"additional","affiliation":[{"name":"Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia"},{"name":"NICM Health Research Institute and School of Science, Western Sydney University, Westmead, NSW 2145, Australia"},{"name":"Woolcock Institute of Medical Research, Macquarie University, Sydney, NSW 2113, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2771-9988","authenticated-orcid":false,"given":"Stewart","family":"Yeung","sequence":"additional","affiliation":[{"name":"Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia"},{"name":"Woolcock Institute of Medical Research, Macquarie University, Sydney, NSW 2113, Australia"},{"name":"Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8380-0123","authenticated-orcid":false,"given":"Kit-Leong","family":"Cheong","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10835","DOI":"10.1039\/D2DT01875F","article-title":"A chemical perspective on the clinical use of platinum-based anticancer drugs","volume":"51","author":"Alassadi","year":"2022","journal-title":"Dalton Trans."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.drup.2012.03.002","article-title":"Collateral sensitivity as a strategy against cancer multidrug resistance","volume":"15","author":"Pluchino","year":"2012","journal-title":"Drug Resist. 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