High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance
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 (MC...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13502 |
| _version_ | 1827355801378881536 |
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| author | Ahlem Zaghmi Erdem Aybay Long Jiang Mingmei Shang Julia Steinmetz‐Späh Fredrik Wermeling Per Kogner Marina Korotkova Päivi Östling Per‐Johan Jakobsson Brinton Seashore‐Ludlow Karin Larsson |
| author_facet | Ahlem Zaghmi Erdem Aybay Long Jiang Mingmei Shang Julia Steinmetz‐Späh Fredrik Wermeling Per Kogner Marina Korotkova Päivi Östling Per‐Johan Jakobsson Brinton Seashore‐Ludlow Karin Larsson |
| author_sort | Ahlem Zaghmi |
| collection | DOAJ |
| description | 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 E2 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. |
| first_indexed | 2024-03-08T04:49:33Z |
| format | Article |
| id | doaj.art-4a29d39e06f844be8b5afb223e6cda70 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-08T04:49:33Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-4a29d39e06f844be8b5afb223e6cda702024-02-08T06:47:52ZengWileyMolecular Oncology1574-78911878-02612024-02-0118231733510.1002/1878-0261.13502High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistanceAhlem Zaghmi0Erdem Aybay1Long Jiang2Mingmei Shang3Julia Steinmetz‐Späh4Fredrik Wermeling5Per Kogner6Marina Korotkova7Päivi Östling8Per‐Johan Jakobsson9Brinton Seashore‐Ludlow10Karin Larsson11Rheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenChildhood Cancer Research Unit, Department of Women's and Children's Health Karolinska Institutet Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenDepartment of Oncology‐Pathology, Science for Life Laboratory Karolinska Institutet Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenDepartment of Oncology‐Pathology, Science for Life Laboratory Karolinska Institutet Stockholm SwedenRheumatology Unit, Department of Medicine, Solna Karolinska Institutet, Karolinska University Hospital Stockholm SwedenHigh‐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 E2 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.https://doi.org/10.1002/1878-0261.13502drug screenMCTSmPGES‐1neuroblastomaPGE2spheroids |
| spellingShingle | Ahlem Zaghmi Erdem Aybay Long Jiang Mingmei Shang Julia Steinmetz‐Späh Fredrik Wermeling Per Kogner Marina Korotkova Päivi Östling Per‐Johan Jakobsson Brinton Seashore‐Ludlow Karin Larsson High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance Molecular Oncology drug screen MCTS mPGES‐1 neuroblastoma PGE2 spheroids |
| title | High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance |
| title_full | High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance |
| title_fullStr | High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance |
| title_full_unstemmed | High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance |
| title_short | High‐content screening of drug combinations of an mPGES‐1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance |
| title_sort | high content screening of drug combinations of an mpges 1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance |
| topic | drug screen MCTS mPGES‐1 neuroblastoma PGE2 spheroids |
| url | https://doi.org/10.1002/1878-0261.13502 |
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