High-content screening of drug combinations of an mPGES-1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance.

Autor: Zaghmi A; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Aybay E; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Jiang L; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Shang M; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Steinmetz-Späh J; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Wermeling F; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Kogner P; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Korotkova M; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Östling P; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden., Jakobsson PJ; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Seashore-Ludlow B; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden., Larsson K; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2024 Feb; Vol. 18 (2), pp. 317-335. Date of Electronic Publication: 2023 Aug 21.
DOI: 10.1002/1878-0261.13502
Abstrakt: High-throughput drug screening enables the discovery of new anticancer drugs. Although monolayer cell cultures are commonly used for screening, their limited complexity and translational efficiency require alternative models. Three-dimensional cell cultures, such as multicellular tumor spheroids (MCTS), mimic tumor architecture and offer promising opportunities for drug discovery. In this study, we developed a neuroblastoma MCTS model for high-content drug screening. We also aimed to decipher the mechanisms underlying synergistic drug combinations in this disease model. Several agents from different therapeutic categories and with different mechanisms of action were tested alone or in combination with selective inhibition of prostaglandin E 2 by pharmacological inhibition of microsomal prostaglandin E synthase-1 (mPGES-1). After a systematic investigation of the sensitivity of individual agents and the effects of pairwise combinations, GFP-transfected MCTS were used in a confirmatory screen to validate the hits. Finally, inhibitory effects on multidrug resistance proteins were examined. In summary, we demonstrate how MCTS-based high-throughput drug screening has the potential to uncover effective drug combinations and provide insights into the mechanism of synergy between an mPGES-1 inhibitor and chemotherapeutic agents.
(© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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