Leveraging multi-organ models for drug combination therapy safety

Article Article scientifique Article Leveraging multi-organ models for drug combination therapy safety eng 2025-12-10 2025-12 author Mieville Valentin 0009-0003-4626-0377 School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland; Translational Research Center in Oncohaematology, Geneva 1211, Switzerland. 855454 author Gubala Jakub School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland; Translational Research Center in Oncohaematology, Geneva 1211, Switzerland. 409064 Section des sciences pharmaceutiques (FARMA) author Han Seungsu School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland. 920616 author Ota Marie School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland. 939376 author Andreu Carbo Mireia School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland; Translational Research Center in Oncohaematology, Geneva 1211, Switzerland; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland. 903532 Département de physiologie cellulaire et métabolisme (PHYME) author Molica Filippo Department of Pathology and Immunology, and Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland. 525132 Département de pathologie et immunologie (PATIM) author Benamran Daniel Alexandre Israel Division of Urology, Geneva University Hospitals, Geneva 1211, Switzerland. 618957 Département de chirurgie (CHIRU) author Kwak Brenda 0000-0003-0015-0044 Department of Pathology and Immunology, and Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland. 113350 Département de pathologie et immunologie (PATIM) author Valerio Massimo Division of Urology, Geneva University Hospitals, Geneva 1211, Switzerland. 405547 Département de chirurgie (CHIRU) author Nowak-Sliwinska Patrycja School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland; Translational Research Center in Oncohaematology, Geneva 1211, Switzerland. Electronic address: patrycja.nowak-sliwinska@unige.ch. 848409 Section des sciences pharmaceutiques (FARMA) 118847 10.1016/j.biopha.2025.118847 41380497 0753-3322 https://linkinghub.elsevier.com/retrieve/pii/S0753332225010418 In this study, we developed a streamlined in vitro platform to assess the systemic toxicity of multidrug combinations within a clinically relevant timeframe, facilitating its application in personalized medicine. By incorporating cellular models that represent major toxicity-sensitive organs, such as the kidney, liver, and heart, we evaluated two previously optimized multidrug combinations (C2 and REMP). Our findings revealed distinct organ-specific toxicity profiles, with some drug-induced toxicities exacerbated upon combination. To evaluate the influence of model complexity, we compared responses between simple proliferative cell lines and more advanced models. Proliferative cell models, while useful for initial toxicity screenings, frequently failed to predict the severity of drug-induced toxicity. For instance, the C2 combination decreased cell viability by 50 % in patient-derived kidney organoids but only by 20 % in HEK293T cells. However, the C2 combination caused a 77 % viability reduction in differentiated hepatocyte spheroids, 32 % more than its effect on non-differentiated hepatocyte-like cells. C2 showed significant release of lactate dehydrogenase compared to 0.1 % DMSO. These findings underscore the critical need for systemic and biologically relevant drug safety assessments in the development of novel drug combinations, regardless of known single-drug safety. Despite some limitations, the platform accurately reproduced known single-drug toxicity profiles, confirming its translational potential. Overall, this biologically relevant approach enables efficient early-stage toxicity screening of drug combinations, supporting a safer development of personalized cancer therapy. Cancer Cardiotoxicity Drug combination Drug-drug interaction Hepatotoxicity In vitro Nephrotoxicity Screening Dewey 540 Dewey 615 Dewey 616.07 Dewey 617 Swiss National Science Foundation Synergistic targeted drug combinations for induction of sensitivity to immune checkpoint inhibitors. 197878 CH 137 Département de pathologie et immunologie 21F 31 Section des sciences pharmaceutiques 17 39 Département de biochimie 144 57 Département de chirurgie 222 false 397 Connexines et pathologies cardiovasculaires 665 1325 Pharmacologie moléculaire Biomedicine & pharmacotherapy 193 1e0bfbb8-b9fe-4b4a-9577-ca0ab29cd56d Article (Published version) Public Mieville_Biomed_Pharm_2025.pdf 5664473 application/pdf CC BY-4.0 b229cbd655fc1f82593ab726ac190de5170a3d6ad42f41ee60282a281785a109 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté des sciences / Section des sciences pharmaceutiques Faculté des sciences / Section de chimie et biochimie / Département de biochimie Faculté de médecine / Section de médecine clinique / Département de chirurgie

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Leveraging multi-organ models for drug combination therapy safety	Biomedicine & pharmacotherapy			2025	30	66

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