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Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy

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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.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We would like to thank the Babol University of medical sciences research committee for supporting this study.

Funding

This study was supported by Babol University of medical sciences grant number 724132610. Ethics committee approval ID: IR.MUBABOL.REC.1400.138.

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Authors and Affiliations

  1. Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Milad Moloudizargari

  2. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Shirin Hekmatirad

  3. Laboratory of Bioinformatics and Drug Design (LBD), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Sajjad Gharaghani

  4. Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, 4717647745, Iran

    Ali Akbar Moghadamnia, Hossein Najafzadehvarzi & Mohammad Hossein Asghari

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Contributions

Conceptualization, MHA and MM; Methodology and Software, SH and SG; Data analysis, MM and AAM; Original draft preparation, SH and HN; Review and editing, MHA; All the authors have read and approved the submitted version.

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Correspondence to Mohammad Hossein Asghari.

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Moloudizargari, M., Hekmatirad, S., Gharaghani, S. et al. Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy. J Cancer Res Clin Oncol 149, 7207–7216 (2023). https://doi.org/10.1007/s00432-023-04674-6

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