{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T04:43:20Z","timestamp":1773117800138,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T00:00:00Z","timestamp":1772841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: P-glycoprotein (P-gp, ABCB1\/MDR1) is a key ATP-binding cassette transporter involved in multidrug resistance in cancer, limiting intracellular accumulation of various chemotherapeutic (CT) agents. Several antidepressants (ADs) have been shown to modulate P-gp function. This dual pharmacological profile raises the possibility of repurposing ADs as chemosensitizers to enhance anticancer drug efficacy. The objective of this review was to summarize the available evidence on the combined use of ADs and chemotherapeutics to overcome P-gp-mediated resistance. Methods: A systematic search was performed in PubMed, Scopus, and PsycInfo\/PsycArticles databases using a comprehensive search string combining terms for P-gp, ADs, chemotherapy, and drug resistance. Inclusion criteria were preclinical or clinical studies investigating the effect of ADs in combination with chemotherapeutics on P-gp-mediated resistance in cancer models. Eleven relevant studies were identified and qualitatively analyzed. Results: Across diverse cancer models, including colon, breast, and multidrug-resistant cell lines, several ADs significantly enhanced the cytotoxicity of many chemotherapeutic agents. The proposed mechanisms involved downregulation of P-gp expression, inhibition of efflux activity, and increased intracellular drug accumulation. Conclusions: The combination of ADs with CT agents shows promising potential in overcoming P-gp-mediated multidrug resistance, enhancing antitumor efficacy in preclinical models. Further translational and clinical research is needed to validate these findings, optimize dosing strategies, and assess the risk\u2013benefit profile in cancer patients, particularly those with comorbid depressive disorders.<\/jats:p>","DOI":"10.3390\/medsci14010126","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T08:58:45Z","timestamp":1773046725000},"page":"126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination of Antidepressants and Chemotherapeutic Agents to Overcome P-Glycoprotein-Mediated Resistance in Cancer Patients: A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"given":"Antonio","family":"Restaino","sequence":"first","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8254-9299","authenticated-orcid":false,"given":"Mario","family":"Pinto","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulio","family":"Carriero","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Maria","family":"D\u2019Onofrio","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Montanari","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delfina","family":"Janiri","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Section of Psychiatry, Department of Neuroscience, Head-Neck and Chest, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-9230","authenticated-orcid":false,"given":"Giovanni","family":"Camardese","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Head-Neck and Chest, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Department of Life Science, Health, and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3176-6060","authenticated-orcid":false,"given":"Lorenzo","family":"Moccia","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Section of Psychiatry, Department of Neuroscience, Head-Neck and Chest, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-8752","authenticated-orcid":false,"given":"Gabriele","family":"Sani","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Section of Psychiatry, Department of Neuroscience, Head-Neck and Chest, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6963-7494","authenticated-orcid":false,"given":"Alessio","family":"Simonetti","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Department of Neuroscience, Head-Neck and Chest, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,7]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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