{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T05:28:16Z","timestamp":1769232496433,"version":"3.49.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. A critical factor contributing to MDR is overexpression of ATP\u2010binding cassette (ABC) transporters, such as ABCB1. Novel alternative therapeutic strategies are needed to overcome resistance associated with ABC transporters. In the present study, we aimed to elucidate the mechanisms by which melatonin overcomes ABCB1\u2010mediated MDR in cancer cells, with a focus on mitochondrial function. We analyzed the effects of melatonin (1\u2009mM) on head and neck squamous cell carcinoma cell lines (CAL 27 and SCC\u20109) overexpressing\n                    <jats:italic>ABCB1<\/jats:italic>\n                    and exhibiting increased resistance to cisplatin (CDDP) compared to their parental cells. To further validate the role of melatonin in reversing ABCB1\u2010mediated MDR, we also evaluated its effects on doxorubicin\u2010resistant MCF\u20107 breast cancer cells. We further examined the potential of melatonin to overcome MDR in CAL 27 xenografted mice. Here, we report that melatonin treatment specifically triggered reactive oxygen species (ROS) production in mitochondria and weakened chemoresistance. ROS oxidized NADH into NAD\n                    <jats:sup>+<\/jats:sup>\n                    , and limiting the availability of ATP for efflux pump activity. Additionally, melatonin decreased the number of mitochondria localized near the nucleus instead of the cytoplasm and downregulated ABCB1 expression. Intratumoral administration of melatonin effectively overcame CDDP resistance in CAL 27\/ABCB1 xenografts, significantly reducing tumor volume and promoting apoptosis. These findings demonstrate that melatonin enhances chemosensitivity in ABCB1\u2010overexpressing cells by modulating mitochondrial metabolism, redox balance, and ABCB1 expression, highlighting its potential as an adjuvant therapy to overcome MDR.\n                  <\/jats:p>","DOI":"10.1111\/jpi.70096","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:58:01Z","timestamp":1762322281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Melatonin Overcomes Cancer Multidrug Resistance by Downregulating ABCB1 Expression and Modulating Mitochondrial Function"],"prefix":"10.1111","volume":"77","author":[{"given":"Alba","family":"L\u00f3pez\u2010Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada Granada Spain"},{"name":"Department of Physiology, Faculty of Medicine University of Granada Granada Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Investigaci\u00f3n Biosanitaria (Ibs), Granada, San Cecilio University Hospital Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Martinez\u2010Ruiz","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada Granada Spain"},{"name":"Department of Physiology, Faculty of Medicine University of Granada Granada Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Investigaci\u00f3n Biosanitaria (Ibs), Granada, San Cecilio University Hospital Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Morales\u2010Gallel","sequence":"additional","affiliation":[{"name":"Cavanilles Institute of Biodiversity and Evolutionary Biology University of Valencia Valencia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Florido","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada Granada Spain"},{"name":"Department of Physiology, Faculty of Medicine University of Granada Granada Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Investigaci\u00f3n Biosanitaria (Ibs), Granada, San Cecilio University Hospital Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiola","family":"Bermejo\u2010Casares","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, Faculty of Medicine University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs. GRANADA Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Manuel","family":"Garcia\u2010Verdugo","sequence":"additional","affiliation":[{"name":"Cavanilles Institute of Biodiversity and Evolutionary Biology University of Valencia Valencia Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Mart\u00edn","family":"Esteban\u00e9","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada Granada Spain"},{"name":"Department of Physiology, Faculty of Medicine University of Granada Granada Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Investigaci\u00f3n Biosanitaria (Ibs), Granada, San Cecilio University Hospital Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00edctor","family":"Carriel","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, Faculty of Medicine University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs. GRANADA Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noelia","family":"Maldonado\u2010P\u00e9rez","sequence":"additional","affiliation":[{"name":"Gene and Cell Therapy Unit, Genomic Medicine Department Pfizer\u2010University of Granada\u2010Junta de Andaluc\u00eda, Centre for Genomics and Oncological Research (GENYO) Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Gonz\u00e1lez\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada Granada Spain"},{"name":"Department of Physiology, Faculty of Medicine University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs. 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