Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2 : implications in blockade of exosome release in cancer therapy
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature..
PURPOSE: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs.
METHODS: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro.
RESULTS: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased.
CONCLUSION: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:149 |
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| Enthalten in: |
Journal of cancer research and clinical oncology - 149(2023), 10 vom: 15. Aug., Seite 7207-7216 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moloudizargari, Milad [VerfasserIn] |
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| Links: |
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| Themen: |
1NF15YR6UY |
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| Anmerkungen: |
Date Completed 31.07.2023 Date Revised 16.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00432-023-04674-6 |
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| 520 | |a © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. | ||
| 520 | |a PURPOSE: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs | ||
| 520 | |a METHODS: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro | ||
| 520 | |a RESULTS: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased | ||
| 520 | |a CONCLUSION: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Najafzadehvarzi, Hossein |e verfasserin |4 aut | |
| 700 | 1 | |a Asghari, Mohammad Hossein |e verfasserin |4 aut | |
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