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- Title
Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy.
- Authors
Moloudizargari, Milad; Hekmatirad, Shirin; Gharaghani, Sajjad; Moghadamnia, Ali Akbar; Najafzadehvarzi, Hossein; Asghari, Mohammad Hossein
- Abstract
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.
- Subjects
SPHINGOMYELINASE; MEDICAL screening; EXOSOMES; CANCER treatment; STANDARD deviations
- Publication
Journal of Cancer Research & Clinical Oncology, 2023, Vol 149, Issue 10, p7207
- ISSN
0171-5216
- Publication type
Article
- DOI
10.1007/s00432-023-04674-6