{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T05:17:34Z","timestamp":1783142254079,"version":"3.54.6"},"reference-count":110,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoX"],"abstract":"<jats:p>Drug repurposing represents a rational and resource-efficient strategy to expand the oncological armamentarium by leveraging the established pharmacology, clinical experience, and safety-monitoring frameworks of approved non-oncological agents. Clozapine (CZP), an atypical antipsychotic characterized by broad receptor pharmacology, complex biotransformation, and clinically relevant toxicological liabilities, has emerged as a candidate of interest following preclinical evidence of context-dependent anticancer activity across multiple tumor types. As such, CZP provides an informative case study at the interface between therapeutic drug action and xenobiotic behavior. This review provides a critical and integrated synthesis of the current evidence supporting the repurposing of CZP in oncology, with particular emphasis on the relationship between its molecular mechanisms, dose\u2013exposure requirements, pharmacological complexity, and potential toxicity. Analysis of in vitro and in vivo studies across glioblastoma, non-small cell lung cancer, breast cancer, and melanoma brain metastasis models indicates that CZP can impair tumor cell proliferation and survival through a form of mechanistic plasticity. Rather than acting through a single conserved pathway, CZP appears to disrupt shared upstream processes related to pro-survival signaling, cellular stress tolerance, and metabolic homeostasis, while engaging tumor-specific downstream responses, including autophagic cell death, mitochondria-dependent apoptosis, oxidative stress, and coordinated modulation of survival and angiogenic pathways. Despite this mechanistic rationale, translation remains substantially constrained, most notably by the order of magnitude gap between anticancer-effective concentrations in vitro and clinically achievable plasma exposures, requiring careful distinction between potentially useful anticancer pharmacology and nonspecific xenobiotic-induced cellular stress and clinically unacceptable toxicity. Key limitations include the discrepancy between anticancer-effective concentrations observed in vitro and exposures achievable during standard psychiatric dosing, the limited understanding of how CZP metabolism and metabolite formation may influence efficacy and toxicity, the absence of integrated pharmacokinetic\u2013pharmacodynamic and toxicokinetic modeling, and the lack of dedicated clinical trial evidence. To address these challenges, this review examines complementary translational strategies, including patient-derived organoids, co-culture systems, microphysiological platforms, pharmacokinetic and toxicological modeling, and computational digital twin frameworks. Together, these approaches may support a biologically informed and risk-aware evaluation of CZP, helping to identify responsive tumor contexts, anticipate exposure-related liabilities, and prioritize rational combination strategies. By integrating therapeutic potential with xenobiotic pharmacology and toxicology, this review positions CZP within the evolving landscape of precision oncology and evidence-driven drug repurposing.<\/jats:p>","DOI":"10.3390\/jox16040125","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:04:44Z","timestamp":1782986684000},"page":"125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Therapeutic Drug to Xenobiotic in Cancer Repurposing: Clozapine Mechanisms, Metabolic Liabilities, and Human-Relevant Translational Approaches"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3747-5520","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Gouveia","sequence":"first","affiliation":[{"name":"PerMed Research Group, RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Placido da Costa, 4200-450 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10732748251378666","DOI":"10.1177\/10732748251378666","article-title":"Alleviating the Global Burden of Cancer Through Prevention and Early Detection","volume":"32","author":"Elbarazi","year":"2025","journal-title":"Cancer Control"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/ijc.33588","article-title":"Cancer Statistics for the Year 2020: An Overview","volume":"149","author":"Ferlay","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1200\/EDBK_158808","article-title":"Tumor Heterogeneity and Therapeutic Resistance","volume":"36","author":"Lovly","year":"2016","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17887","DOI":"10.1038\/s41598-023-44264-7","article-title":"Drug Repurposing: A Nexus of Innovation, Science, and Potential","volume":"13","author":"Purohit","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pinzi, L., Bisi, N., and Rastelli, G. (2024). How Drug Repurposing Can Advance Drug Discovery: Challenges and Opportunities. Front. Drug Discov., 4.","DOI":"10.3389\/fddsv.2024.1460100"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1080\/17460441.2020.1704729","article-title":"Challenges and Opportunities with Drug Repurposing: Finding Strategies to Find Alternative Uses of Therapeutics","volume":"15","author":"Talevi","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.schres.2004.06.016","article-title":"Cancer in Schizophrenia: Is the Risk Higher or Lower?","volume":"73","author":"Grinshpoon","year":"2005","journal-title":"Schizophr. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1002\/cncr.21574","article-title":"Reduced Cancer Incidence among Patients with Schizophrenia","volume":"104","author":"Barak","year":"2005","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104809","DOI":"10.1016\/j.neubiorev.2022.104809","article-title":"Treatment of Cancer with Antipsychotic Medications: Pushing the Boundaries of Schizophrenia and Cancer","volume":"141","author":"Brown","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_10","first-page":"233","article-title":"Antipsychotics Repurposing Offers Novel Advances in Cancer Treatment","volume":"16","author":"Mahmoud","year":"2025","journal-title":"Int. J. Pharm. Qual. Assur."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s40199-025-00562-1","article-title":"Drug Repositioning: Examining Antipsychotic Drugs and Their Anticancer Effects","volume":"33","author":"Sagnak","year":"2025","journal-title":"DARU J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/14737140.2022.1987221","article-title":"Repurposing Antipsychotic Drugs for Cancer Treatment: Current Evidence and Future Perspectives","volume":"22","author":"Lianos","year":"2022","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Waszkiewicz, N. (2025). The Future of Oncology in Psychiatric Medications. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176003"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s12672-025-02067-4","article-title":"Repurposing of Nervous System Drugs for Cancer Treatment: Recent Advances, Challenges, and Future Perspectives","volume":"16","author":"Wang","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.7150\/ijbs.32625","article-title":"The Antipsychotic Agent Flupentixol Is a New PI3K Inhibitor and Potential Anticancer Drug for Lung Cancer","volume":"15","author":"Dong","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.21873\/anticanres.11085","article-title":"Aripiprazole, an Antipsychotic and Partial Dopamine Agonist, Inhibits Cancer Stem Cells and Reverses Chemoresistance","volume":"36","author":"Suzuki","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1158\/1535-7163.MCT-23-0449","article-title":"The Antipsychotic Drug Penfluridol Inhibits N-Linked Glycoprotein Processing and Enhances T-Cell\u2013Mediated Tumor Immunity","volume":"23","author":"Xu","year":"2024","journal-title":"Mol. Cancer Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.4103\/ijnpnd.IJNPND_82_21","article-title":"Antiproliferative Effects of Olanzapine against MCF-7 Cells and Its Molecular Interactions with Survivin","volume":"12","author":"Vedam","year":"2022","journal-title":"Int. J. Nutr. Pharmacol. Neurol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gammon, D., Cheng, C., Volkovinskaia, A., Baker, G.B., and Dursun, S.M. (2021). Clozapine: Why Is It So Uniquely Effective in the Treatment of a Range of Neuropsychiatric Disorders?. Biomolecules, 11.","DOI":"10.3390\/biom11071030"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/bs.apha.2017.09.009","article-title":"Unique Effects of Clozapine: A Pharmacological Perspective","volume":"82","author":"Khokhar","year":"2018","journal-title":"Advances in Pharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"N\u0103stase, M.-G., Vasile, A.I., Pietreanu, A.C., and Trifu, S. (2025). Following the Action of Atypical Antipsychotic Clozapine and Possible Prediction of Treatment Response in Schizophrenia. Life, 15.","DOI":"10.3390\/life15060830"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s40263-017-0411-6","article-title":"Clozapine for Treatment-Resistant Schizophrenia: Still the Gold Standard?","volume":"31","author":"Taylor","year":"2017","journal-title":"CNS Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.neubiorev.2017.09.027","article-title":"Dopamine, the Antipsychotic Molecule: A Perspective on Mechanisms Underlying Antipsychotic Response Variability","volume":"85","author":"Amato","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_24","first-page":"100140","article-title":"Clozapine: A Special Case of an Atypical Antipsychotic","volume":"10","author":"Marinho","year":"2024","journal-title":"Eur. J. Med. Chem. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/S0304-3940(00)01225-8","article-title":"Clozapine Downregulates 5-Hydroxytryptamine6 (5-HT6) and Upregulates 5-HT7 Receptors in HeLa Cells","volume":"288","author":"Zhukovskaya","year":"2000","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1177\/02698811251319458","article-title":"The Mechanism of Action of Clozapine","volume":"39","author":"Morrison","year":"2025","journal-title":"J. Psychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"268","DOI":"10.21147\/j.issn.1000-9604.2025.02.11","article-title":"Context-Dependent Roles of 5-HT and Its Receptors in Tumor Growth and Wound Healing: Mechanisms and Therapeutic Implications","volume":"37","author":"Zeng","year":"2025","journal-title":"Chin. J. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1093\/carcin\/bgac045","article-title":"Understanding the Role of Dopamine in Cancer: Past, Present and Future","volume":"43","author":"Grant","year":"2022","journal-title":"Carcinogenesis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5296","DOI":"10.7150\/thno.55986","article-title":"Role of Serotonin Receptor Signaling in Cancer Cells and Anti-Tumor Immunity","volume":"11","author":"Karmakar","year":"2021","journal-title":"Theranostics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.neuroscience.2024.12.014","article-title":"The Dual Role of Dopamine and Serotonin in Cancer Progression and Inflammation: Mechanisms and Therapeutic Potential","volume":"569","author":"Ahangari","year":"2025","journal-title":"Neuroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/978-3-642-23274-9_19","article-title":"Muscarinic Receptor Agonists and Antagonists: Effects on Cancer","volume":"208","author":"Fryer","year":"2012","journal-title":"Muscarinic Receptors"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103573","DOI":"10.1016\/j.jpet.2025.103573","article-title":"Histamine H1 Receptor: A Potential Therapeutic Target for Pancreatic Ductal Adenocarcinoma","volume":"392","author":"Sriram","year":"2025","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s12964-021-00755-6","article-title":"Role of \u03b1- and \u03b2-Adrenergic Signaling in Phenotypic Targeting: Significance in Benign and Malignant Urologic Disease","volume":"19","author":"Archer","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118637","DOI":"10.1016\/j.biopha.2025.118637","article-title":"Role of Adrenergic Receptors and Their Blocking in Cancer Research","volume":"192","author":"Gazova","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Calaf, G.M., Crispin, L.A., Mu\u00f1oz, J.P., Aguayo, F., and Bleak, T.C. (2022). Muscarinic Receptors Associated with Cancer. Cancers, 14.","DOI":"10.3390\/cancers14092322"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1038\/s41388-019-1093-y","article-title":"Upregulation of Histamine Receptor H1 Promotes Tumor Progression and Contributes to Poor Prognosis in Hepatocellular Carcinoma","volume":"39","author":"Zhao","year":"2020","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.2165\/00003088-199324020-00005","article-title":"Pharmacokinetics and Pharmacodynamics of Clozapine","volume":"24","author":"Jann","year":"1993","journal-title":"Clin. Pharmacokinet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1046\/j.1365-2125.1998.00822.x","article-title":"Pharmacokinetics of Clozapine and Its Metabolites in Psychiatric Patients: Plasma Protein Binding and Renal Clearance","volume":"46","author":"Schaber","year":"1998","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/S0022-3565(25)24566-9","article-title":"Metabolism and Bioactivation of Clozapine by Human Liver in vitro","volume":"272","author":"Pirmohamed","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1124\/dmd.112.050484","article-title":"Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine","volume":"41","author":"Dragovic","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3163502","DOI":"10.1155\/2019\/3163502","article-title":"Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia","volume":"2019","author":"Olmos","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_42","unstructured":"(2026, June 21). Available online: https:\/\/go.drugbank.com\/drugs\/DB00363."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jconrel.2005.06.006","article-title":"Pharmacokinetics, Tissue Distribution and Bioavailability of Clozapine Solid Lipid Nanoparticles after Intravenous and Intraduodenal Administration","volume":"107","author":"Manjunath","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0024-3205(02)01680-6","article-title":"In Vitro P-Glycoprotein Affinity for Atypical and Conventional Antipsychotics","volume":"71","author":"Boulton","year":"2002","journal-title":"Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00213-006-0437-9","article-title":"Evaluation of Antipsychotic Drugs as Inhibitors of Multidrug Resistance Transporter P-Glycoprotein","volume":"187","author":"Wang","year":"2006","journal-title":"Psychopharmacology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1111\/j.1742-7843.2008.00298.x","article-title":"Antipsychotic Drugs Inhibit the Function of Breast Cancer Resistance Protein","volume":"103","author":"Wang","year":"2008","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/bcp.15691","article-title":"A Population Pharmacokinetic Model to Guide Clozapine Dose Selection, Based on Age, Sex, Ethnicity, Body Weight and Smoking Status","volume":"90","author":"Reeves","year":"2024","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1016\/j.cellsig.2006.02.004","article-title":"Clozapine, a Neuroleptic Agent, Inhibits Akt by Counteracting Ca2+\/Calmodulin in PTEN-Negative U-87MG Human Glioblastoma Cells","volume":"18","author":"Shin","year":"2006","journal-title":"Cell. Signal."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Moura, C., Gouveia, M.J., and Vale, N. (2025). Repurposed Antipsychotics as Potential Anticancer Agents: Clozapine Efficacy and Dopaminergic Pathways in Neuroblastoma and Glioblastoma. Life, 15.","DOI":"10.3390\/life15071097"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s10585-025-10328-3","article-title":"Repurposing Neuroleptics: Clozapine as a Novel, Adjuvant Therapy for Melanoma Brain Metastases","volume":"42","author":"Wikerholmen","year":"2025","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jdermsci.2013.07.012","article-title":"Antitumor Activity of Histamine and Clozapine in a Mouse Experimental Model of Human Melanoma","volume":"72","author":"Massari","year":"2013","journal-title":"J. Dermatol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1159\/000369751","article-title":"Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells","volume":"35","author":"Yin","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Fan, Y.-C., Lin, S.-C., Lai, P.-J., Lai, P.-C., Maurus, G., and Chen, S.-Y. (2025). A Psychiatric Medication, Clozapine, Induces Autophagy and Apoptosis in Breast Cancer Cells through Reactive Oxygen Species. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0326224"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"117931","DOI":"10.1016\/j.biopha.2025.117931","article-title":"Unlocking the Molecular Mechanisms of Anticancer and Immunomodulatory Potentials of Cariprazine in Triple Negative Breast Cancer","volume":"184","author":"Lazovic","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3892\/ijo.2022.5359","article-title":"Signaling Pathways and Therapeutic Approaches in Glioblastoma Multiforme","volume":"60","author":"Khabibov","year":"2022","journal-title":"Int. J. Oncol."},{"key":"ref_56","first-page":"1158","article-title":"Revisiting Strategies to Target ABC Transporter-Mediated Drug Resistance in CNS Cancer","volume":"22","author":"Amawi","year":"2025","journal-title":"Cancer Biol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Perazzoli, G., Prados, J., Ortiz, R., Caba, O., Cabeza, L., Berdasco, M., G\u00f3nzalez, B., and Melguizo, C. (2015). Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140131"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s40495-016-0072-z","article-title":"Challenges in the Delivery of Therapies to Melanoma Brain Metastases","volume":"2","author":"Gampa","year":"2016","journal-title":"Curr. Pharmacol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1002\/2211-5463.13730","article-title":"Acquired and Intrinsic Resistance to Vemurafenib in BRAFV600E-driven Melanoma Brain Metastases","volume":"14","author":"Zhang","year":"2024","journal-title":"FEBS Open Bio"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Vlachos, N., Lampros, M., Voulgaris, S., and Alexiou, G.A. (2021). Repurposing Antipsychotics for Cancer Treatment. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121785"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41392-024-01808-1","article-title":"Drug Repurposing for Cancer Therapy","volume":"9","author":"Xia","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41392-020-00213-8","article-title":"Overcoming Cancer Therapeutic Bottleneck by Drug Repurposing","volume":"5","author":"Zhang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Stenvang, J., K\u00fcmler, I., Nyg\u00e5rd, S.B., Smith, D.H., Nielsen, D., Br\u00fcnner, N., and Moreira, J.M.A. (2013). Biomarker-Guided Repurposing of Chemotherapeutic Drugs for Cancer Therapy: A Novel Strategy in Drug Development. Front. Oncol., 3.","DOI":"10.3389\/fonc.2013.00313"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nrclinonc.2011.121","article-title":"Predictive Biomarkers: A Paradigm Shift towards Personalized Cancer Medicine","volume":"8","author":"Kerr","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Motohashi, S., Katsuta, E., and Ban, D. (2025). Advances and Challenges in Drug Screening for Cancer Therapy: A Comprehensive Review. Bioengineering, 12.","DOI":"10.3390\/bioengineering12121315"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s41416-023-02502-9","article-title":"Unlocking Hidden Potential: Advancements, Approaches, and Obstacles in Repurposing Drugs for Cancer Therapy","volume":"130","author":"Weth","year":"2024","journal-title":"Br. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"14158","DOI":"10.18632\/oncotarget.13258","article-title":"Unveiling Changes in the Landscape of Patient Populations in Cancer Early Drug Development","volume":"8","author":"Hierro","year":"2017","journal-title":"Oncotarget"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Rodrigues, R., Duarte, D., and Vale, N. (2022). Drug Repurposing in Cancer Therapy: Influence of Patient\u2019s Genetic Background in Breast Cancer Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084280"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1056\/NEJM199307153290303","article-title":"Clozapine-Induced Agranulocytosis\u2014Incidence and Risk Factors in the United States","volume":"329","author":"Alvir","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1111\/acps.12898","article-title":"Meta-analysis Examining the Epidemiology of Clozapine-associated Neutropenia","volume":"138","author":"Myles","year":"2018","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"525","DOI":"10.2147\/NDT.S502312","article-title":"A Review of Clinical Advances and Challenges in Clozapine-Induced Myocarditis","volume":"21","author":"Li","year":"2025","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3371\/1935-1232.10.3.163","article-title":"Guide to the Management of Clozapine-Related Tolerability and Safety Concerns","volume":"10","author":"Citrome","year":"2016","journal-title":"Clin. Schizophr. Relat. Psychoses"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Yuen, J.W.Y., Kim, D.D., Procyshyn, R.M., White, R.F., Honer, W.G., and Barr, A.M. (2018). Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00203"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1742-7843.2007.00017.x","article-title":"Metabolic Drug Interactions with Newer Antipsychotics: A Comparative Review","volume":"100","author":"Spina","year":"2007","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1007\/s40262-019-00797-7","article-title":"Correction to: Clinical Pharmacokinetics of Atypical Antipsychotics: An Update","volume":"58","author":"Mauri","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"33","DOI":"10.12793\/tcp.2021.29.e3","article-title":"Physiologically-Based Pharmacokinetic Model for Clozapine in Korean Patients with Schizophrenia","volume":"29","author":"Lee","year":"2021","journal-title":"Transl. Clin. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1055\/a-2560-4028","article-title":"Therapeutic Reference Range for Clozapine Plasma Levels in Parkinson\u2019s Disease or Dementia: A Systematic Review and Individual Participant Data Meta-Analysis","volume":"58","author":"Kuzo","year":"2025","journal-title":"Pharmacopsychiatry"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1158\/0008-5472.CAN-13-2971","article-title":"Cancer Cell Lines for Drug Discovery and Development","volume":"74","author":"Wilding","year":"2014","journal-title":"Cancer Res."},{"key":"ref_79","first-page":"114","article-title":"Lost in Translation: Animal Models and Clinical Trials in Cancer Treatment","volume":"6","author":"Mak","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Colonna, G. (2025). Overcoming Barriers in Cancer Biology Research: Current Limitations and Solutions. Cancers, 17.","DOI":"10.3390\/cancers17132102"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrd2110","article-title":"The Mighty Mouse: Genetically Engineered Mouse Models in Cancer Drug Development","volume":"5","author":"Sharpless","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1200\/EDBK_180460","article-title":"Pharmacokinetic\/Pharmacodynamic Modeling for Drug Development in Oncology","volume":"37","author":"Garralda","year":"2017","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000507638","article-title":"A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology","volume":"89","author":"Ruan","year":"2020","journal-title":"Psychother. Psychosom."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2165\/00023210-199707020-00005","article-title":"Mechanism of Clozapine-Induced Agranulocytosis: Current Status of Research and Implications for Drug Development","volume":"7","author":"Pirmohamed","year":"1997","journal-title":"CNS Drugs"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/S0022-3565(25)12206-4","article-title":"The Metabolic Formation of Reactive Intermediates from Clozapine, a Drug Associated with Agranulocytosis in Man","volume":"275","author":"Maggs","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Willcocks, I.R., Legge, S.E., Nalmpanti, M., Mazzeo, L., King, A., Jansen, J., Helthuis, M., Owen, M.J., O\u2019Donovan, M.C., and Walters, J.T.R. (2021). Clozapine Metabolism Is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.658734"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e13930","DOI":"10.1016\/j.heliyon.2023.e13930","article-title":"Myocarditis in Patients on Long-Term Antipsychotics\u2014Mechanism, Management and Recent Updates","volume":"9","author":"Daniel","year":"2023","journal-title":"Heliyon"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1038\/s41380-025-02935-z","article-title":"Examination of Mitochondria- and Inflammasome-Mediated Mechanisms of Clozapine-Induced Myocarditis Using Patient-Derived iPSC Cardiomyocytes","volume":"30","author":"Vaziri","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.2217\/fon-2023-0513","article-title":"The Impact of Myelosuppression on Quality of Life of Patients Treated with Chemotherapy","volume":"20","author":"Crawford","year":"2024","journal-title":"Future Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1158\/1078-0432.CCR-16-3083","article-title":"Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies","volume":"23","author":"Liston","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Matteoni, S., Matarrese, P., Ascione, B., Buccarelli, M., Ricci-Vitiani, L., Pallini, R., Villani, V., Pace, A., Paggi, M.G., and Abbruzzese, C. (2021). Anticancer Properties of the Antipsychotic Drug Chlorpromazine and Its Synergism With Temozolomide in Restraining Human Glioblastoma Proliferation In Vitro. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.635472"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e468","DOI":"10.1016\/j.wneu.2019.04.180","article-title":"Synergistic Suppression of Glioblastoma Cell Growth by Combined Application of Temozolomide and Dopamine D2 Receptor Antagonists","volume":"128","author":"Liu","year":"2019","journal-title":"World Neurosurg."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Mokhtari, R.B., Sambi, M., Shekari, F., Satari, K., Ghafoury, R., Ashayeri, N., Eversole, P., Baluch, N., Harless, W.W., and Muscarella, L.A. (2025). A Comprehensive Oncological Biomarker Framework Guiding Precision Medicine. Biomolecules, 15.","DOI":"10.3390\/biom15091304"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41523-026-00904-5","article-title":"Dynamic Biomarkers in Hormone Receptor-Positive\/HER2-Negative Breast Cancer Trials: A New Hope for Precision Oncology","volume":"12","author":"Pascual","year":"2026","journal-title":"npj Breast Cancer"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3892\/ijo.2025.5789","article-title":"Nanoparticle-based Delivery Systems for Targeted Therapy in Brain Tumors: Progress, Challenges and Perspectives (Review)","volume":"67","author":"Si","year":"2025","journal-title":"Int. J. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"512","DOI":"10.34172\/apb.2023.062","article-title":"Drug Delivery of Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) to Target Brain Tumors","volume":"13","author":"Mehrdadi","year":"2023","journal-title":"Adv. Pharm. Bull."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2174\/138920007779816002","article-title":"Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy","volume":"8","author":"Lin","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_98","first-page":"1163","article-title":"Clinical Pharmacology of Atypical Antipsychotics: An Update","volume":"13","author":"Mauri","year":"2014","journal-title":"EXCLI J."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Zhao, R., Feng, Q., Xia, Y., Liao, L., and Xie, S. (2025). Iteration of Tumor Organoids in Drug Development: Simplification and Integration. Pharmaceuticals, 18.","DOI":"10.3390\/ph18101540"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cell.2016.05.082","article-title":"Modeling Development and Disease with Organoids","volume":"165","author":"Clevers","year":"2016","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"105171","DOI":"10.1016\/j.critrevonc.2026.105171","article-title":"Digital Twins in Oncology: From Predictive Modelling to Personalised Treatment Strategies","volume":"220","author":"Olawade","year":"2026","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"101028","DOI":"10.1016\/j.patter.2024.101028","article-title":"Concepts and Applications of Digital Twins in Healthcare and Medicine","volume":"5","author":"Zhang","year":"2024","journal-title":"Patterns"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1002\/psp4.13093","article-title":"Virtual Twins for Model-informed Precision Dosing of Clozapine in Patients with Treatment-resistant Schizophrenia","volume":"13","author":"Mostafa","year":"2024","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/psp4.12886","article-title":"Delineating Gene\u2013Environment Effects Using Virtual Twins of Patients Treated with Clozapine","volume":"12","author":"Mostafa","year":"2023","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/s41746-025-02115-x","article-title":"The Role of Digital Twins in P4 Medicine: A Paradigm for Modern Healthcare","volume":"8","author":"Parkkila","year":"2025","journal-title":"npj Digit. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41746-024-01073-0","article-title":"Digital Twins for Health: A Scoping Review","volume":"7","author":"Katsoulakis","year":"2024","journal-title":"npj Digit. Med."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Silva, A., and Vale, N. (2025). Digital Twins in Personalized Medicine: Bridging Innovation and Clinical Reality. J. Pers. Med., 15.","DOI":"10.3390\/jpm15110503"},{"key":"ref_108","first-page":"100409","article-title":"Transformative Roles of Digital Twins from Drug Discovery to Continuous Manufacturing: Pharmaceutical and Biopharmaceutical Perspectives","volume":"10","author":"Maharjan","year":"2025","journal-title":"Int. J. Pharm. X"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Kamel Boulos, M.N., and Zhang, P. (2021). Digital Twins: From Personalised Medicine to Precision Public Health. J. Pers. Med., 11.","DOI":"10.3390\/jpm11080745"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13073-025-01435-7","article-title":"Digital Twins as Global Learning Health and Disease Models for Preventive and Personalized Medicine","volume":"17","author":"Li","year":"2025","journal-title":"Genome Med."}],"container-title":["Journal of Xenobiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4713\/16\/4\/125\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T04:47:14Z","timestamp":1783140434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4713\/16\/4\/125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":110,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jox16040125"],"URL":"https:\/\/doi.org\/10.3390\/jox16040125","relation":{},"ISSN":["2039-4713"],"issn-type":[{"value":"2039-4713","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}