Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy
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: |
Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:149 |
|---|---|
| Enthalten in: |
Journal of cancer research and clinical oncology - 149(2023), 10 vom: 08. März, Seite 7207-7216 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Moloudizargari, Milad [VerfasserIn] |
|---|
| Links: |
Volltext [lizenzpflichtig] |
|---|
| Themen: |
Aprepitant |
|---|
| Anmerkungen: |
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
|---|
| doi: |
10.1007/s00432-023-04674-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
OLC2144702179 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | OLC2144702179 | ||
| 003 | DE-627 | ||
| 005 | 20240118100444.0 | ||
| 007 | tu | ||
| 008 | 240118s2023 xx ||||| 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00432-023-04674-6 |2 doi | |
| 035 | |a (DE-627)OLC2144702179 | ||
| 035 | |a (DE-He213)s00432-023-04674-6-p | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | 4 | |a 610 |q VZ |
| 082 | 0 | 4 | |a 610 |q VZ |
| 100 | 1 | |a Moloudizargari, Milad |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. | ||
| 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. 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. | ||
| 650 | 4 | |a Aprepitant | |
| 650 | 4 | |a Drug repositioning | |
| 650 | 4 | |a Neutral sphingomyelinase 2 | |
| 650 | 4 | |a Exosomes | |
| 650 | 4 | |a Drug resistance | |
| 700 | 1 | |a Hekmatirad, Shirin |4 aut | |
| 700 | 1 | |a Gharaghani, Sajjad |4 aut | |
| 700 | 1 | |a Moghadamnia, Ali Akbar |4 aut | |
| 700 | 1 | |a Najafzadehvarzi, Hossein |4 aut | |
| 700 | 1 | |a Asghari, Mohammad Hossein |0 (orcid)0000-0003-2981-879X |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of cancer research and clinical oncology |d Springer Berlin Heidelberg, 1979 |g 149(2023), 10 vom: 08. März, Seite 7207-7216 |w (DE-627)129330493 |w (DE-600)134792-5 |w (DE-576)014586762 |x 0171-5216 |7 nnns |
| 773 | 1 | 8 | |g volume:149 |g year:2023 |g number:10 |g day:08 |g month:03 |g pages:7207-7216 |
| 856 | 4 | 1 | |u https://doi.org/10.1007/s00432-023-04674-6 |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a SYSFLAG_A | ||
| 912 | |a GBV_OLC | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a GBV_ILN_287 | ||
| 912 | |a GBV_ILN_2018 | ||
| 912 | |a GBV_ILN_4277 | ||
| 951 | |a AR | ||
| 952 | |d 149 |j 2023 |e 10 |b 08 |c 03 |h 7207-7216 | ||