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. 2023 Mar 8;149(10):7207–7216. doi: 10.1007/s00432-023-04674-6

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

Milad Moloudizargari 1, Shirin Hekmatirad 2, Sajjad Gharaghani 3, Ali Akbar Moghadamnia 4, Hossein Najafzadehvarzi 4, Mohammad Hossein Asghari 4,✉
PMCID: PMC11797456  PMID: 36884117

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.

Keywords: Aprepitant, Drug repositioning, Neutral sphingomyelinase 2, Exosomes, Drug resistance

Introduction

Amid tumor progression and development, cancer cells are not the sole culprits. Other factors present within the tumor microenvironment, such as the stromal and immune cells, as well as their secretions contribute to the malignant progression via shaping a tumor-supporting network. This reciprocal interaction is facilitated by the soluble factors secreted by various cell populations within the tumor milieu (Baghban et al. 2020). Exosomes are among the major secreted factors, which enable local and distant communication of such a network, including but not limited to cargo exchange. These nano-sized vesicles are shed nearly by all cell types in both physiologic and pathologic conditions. Various kinds of cargo comprising proteins, nucleic acids, and lipids are packaged in the donor cell and exported to fulfill certain programmed goal. Hence, in addition to their general markers such as tetraspanins, exosomes bear donor cell-specific markers (Moloudizargari et al. 2019a, b, 2021). The reprogramming subsequent to the communication of cancer cells and their surrounding microenvironment leads to episodes of metastasis, angiogenesis, and drug resistance, which altogether act in favor of tumor progression and invasion. In this regard, it has been shown that cancer cells’ exosome secretion occurs at higher levels than normal cells, and they also bear different molecular profiles (Moloudizargari et al. 2018).

As shown in our previous work, exosome secretion could affect both donor and recipient cells (Hekmatirad et al. 2021). Besides the effects of exosomes in the recipient cells due to exosome uptake, via shedding of chemotherapeutic drugs out of the cells, exosomes also confer drug resistance in the original exosome-secreting cells. Therefore, attempts to find efficient exosome inhibitors, and more specifically, exosome release inhibitors is of current interest (Hekmatirad et al. 2021). Exosome biogenesis is mediated through the endosomal sorting complexes required for transport (ESCRT)-dependent and -independent pathways. Exosomes may face two different fates during their biogenesis and maturation. Upon invagination of the plasma membrane, intraluminal vesicles (ILVs) are formed and matured into multi vesicular bodies (MVBs), which either fuse with lysosomes in order for the decomposition of their cargo or merge with the plasma membrane to release their vesicles, the so-called exosomes (Ni et al. 2020). At least in the disease context, the ESCRT-independent pathway, also known as the ceramide pathway, is the main pathway regulating MVB fusion with the plasma membrane and finally exosome release (Trajkovic et al. 2008). In support of this statement, a study on Alzheimer’s disease pathological spread has shown that ceramide-dependent exosomes are involved in disease-supporting conditions rather than brain’s normal functions (Bilousova et al. 2020).nSMase2 is the main enzyme involved in ceramide biosynthesis in Homo sapiens cells. Various nSMase2 inhibitors have been developed and shown successful decrease in exosome secretion (Tallon et al. 2022). However, due to issues like low potency and solubility, currently there is no clinical-grade compound and the tested compounds have only been used in preclinical settings (Rojas et al. 2019). To overcome the problem of safety profile of nSMase2 inhibitor candidates, drug repositioning is a promising approach, saving budget and time. Here, we performed a virtual screening of an FDA-approved library to find and validate a safe and efficient nSMase2 inhibitor.

Materials and methods

Virtual screening

The 3-D structure of nSMase2 (PDB:5uvg) was acquired from the Protein Data Bank (PDB). Next, the macromolecule preparations were performed by removing the water molecules and heteroatoms as well as adding Kollman charge and non-polar hydrogens merging. A library of FDA-approved drugs obtained from Zinc-15 database was used for the screening. The PyRx software was used to minimize the energy of the macromolecule and its ligands. Then, virtual screening was performed via PyRx. The interaction and conformations were studied using Discovery Studio Visualizer. Finally, the compounds were rank-ordered based on the retrieved docking scores and RMSD, and the top compound was selected accordingly.

Molecular docking

To validate the result of virtual screening, molecular docking was performed using AutoDockTools (ADT) for the selected compound. Aprepitant 2D structure was converted into pdb format using Marvin 15.10.12.0 software. The protein and ligand were prepared by University of California, San Francisco (UCSF) Chimera software. Finally, docking was performed using Lamarckian genetic algorithm (Butt et al. 2020).

Molecular dynamics

Molecular dynamic simulation was conducted by the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) software using the aprepitant–nSMase2 complex, obtained from the docking studies.

Cell culture

The color cancer cell line, HCT116 was used for the cell-based studies. The cells were cultured in Dulbecco’s modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin. The cells were used for the experiments at a viability of higher than 95% and a confluency of maximum 70%, and the medium of the cells was replaced with fresh medium 24 h prior to the initiation of each experiment. All the experiments using cells were performed at least in triplicate.

In vitro inhibition studies

To study the inhibitory effects of aprepitant in vitro, a commercial fluorometric assay kit (ab138877, Abcam) was used as described in (Im et al. 2019). The kit uses the production of phosphocholine by sphingomyelinase to indirectly measure the concentration, which is per se a reflection of the enzyme activity. To study the inhibitory effects of aprepitant in both cell-based and cell-free conditions, the experiment was performed once using the cell lysate from the HCT116 cells treated for 24 h with aprepitant and once using the sole assay reagents. Briefly, either the cell lysate prepared using radio-immunoprecipitation assay (RIPA) lysis buffer or the enzyme supplied within the kit was reacted, either in the presence or absence of aprepitant, with the other assay detection reagents according to the protocols recommended by the manufacturer with slight modifications. Following the incubation time, the fluorescence intensity was measured at an excitation/emission of 540/590 nm using a microplate reader. The commercial nSMase2 inhibitor, GW4869 (20 µM) was used as a positive control. All the experiments were performed at least in triplicate.

Statistical analysis

One-way analysis of variances (ANOVA) followed by a Tukey post hoc test was used to determine the statistical differences between groups. P ≤ 0.05 was deemed to be statistically significant. Both the statistical analysis and preparation of illustrations were performed using the GraphPad PRISM Version 9.

Results

Virtual screening

A library of FDA-approved drugs was screened against nSMase2 using the PyRx software. For each compound, a binding affinity and an RMSD score were obtained. Based on the results, the following compounds were identified to have the best scores and were rank ordered from 1 to 10 respectively: aprepitant, rolapitant, dihydroergotamine, ponatinib, ledipasvir, differin, noxafil, elbasvir, conivaptan, and plerixafor. Among the identified compounds, aprepitant had the best scores and was therefore selected for further experiments (Table 1).

Table 1.

Scores and structure of the top 10 drugs acquired from screening

graphic file with name 432_2023_4674_Tab1a_HTML.jpg

graphic file with name 432_2023_4674_Tab1b_HTML.jpg

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Rmsd/ub root-mean-square deviation/upper bound, Rmsd/lb root-mean-square deviation/lower bound

Molecular docking

The results obtained from molecular docking were in line with she screening studies supporting the selection of aprepitant as the best candidate for subsequent in vitro experiments. Two-dimensional (2D) and three-dimensional (3D) interactions of the aprepitant and nSMas2 complex are depicted in Fig. 1.

Fig. 1.

Fig. 1

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Two-dimensional (A) and three-dimensional (B) presentation of aprepitant interactions with nSMase2. The presentations are produced by discovery studio visualizer v16.1.0. Different colors specify interaction types

Molecular dynamics

From a physical point of view, the convergence of the RMSD (Fig. 2A) value indicates the validity of the simulation settings applied in the present study, such as structure modeling and definition of interatomic interactions. This convergence indicates the existence of an attractive force between different parts of the structure and its stability in environmental conditions. As shown in Fig. 2B, the hydrogen bonding pattern of the complex has a stable profile in the course of the simulation (Obaidullah et al. 2022).

Fig. 2.

Fig. 2

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Molecular dynamics simulation results with respect to RMSD and H-bonds. Backbone RMSD investigation of aprepitant–nSMase2 (A). Number of H bonds within the aprepitant–nSMase2 complex (B). RMSD root-mean-square deviation, HB hydrogen bonds

The half-maximal inhibitory concentration (IC50) studies and the highest non-toxic concentrations of aprepitant

To validate our findings from the virtual screening, the IC50 of aprepitant was first calculated in a cancer cell line. HCT116 colorectal carcinoma cells were treated with different concentrations of aprepitant (15, 30, 60, 120, 240, 480, and 960 µM) for 24 h (Fig. 3). The IC50 value obtained from the CCK-8 assay was calculated as 212.4 µM using GraphPad Prism (version 9). Based on the obtained viability curve, a range of highest non-lethal concentrations were selected for subsequent enzymatic experiments.

Fig. 3.

Fig. 3

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Cell viability analysis of HCT116 cells treated with different concentrations of aprepitant for 24 h

Effect of aprepitant on the activity the nSMase2 enzyme

To confirm the prediction results indicating that aprepitant could potentially inhibit nSMase2 activity, a commercial enzyme activity assay kit was used. As shown in Fig. 4, nSMase2 activity was significantly decreased following incubation of different concentrations of aprepitant in the cell-free (reaction mixture) assay with 15 and 30 µM sphingomyelin, the natural substrate of the enzyme. Next, HCT116 cells were treated with similar concentrations of aprepitant, and the nSMase2 activity was measured in a cell-based assay following 24 h (Fig. 5). The results were in line with the reaction mixture assay. Taken together, both cell-based and cell-free assays indicated that the inhibitory effect of aprepitant on nSMase2 activity was as potent as that of the well-known commercially available inhibitor, GW4869.

Fig. 4.

Fig. 4

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The cell-free (reaction mixture) assay for enzyme activity evaluation following incubation with 15 µM (left) and 30 µM (right) sphingomyelin

Fig. 5.

Fig. 5

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Cell-based assay for enzyme activity evaluation following treating HCT116 cells with 15, 30, and 60 µM aprepitant for 24 h

Discussion

Despite achievements of various treatment options like chemotherapy, radiotherapy, targeted therapy, immunotherapy and surgery in cancer patients, almost all of these treatments face a similar problem, drug resistance. Drug resistance leads to most of cancer relapses, worldwide (Wang et al. 2019). Based on the different underlying mechanisms involved in drug resistance like genetic/epigenetic mutations, heterogeneity of tumor cells, increased drug efflux, etc. as well as the timing of resistance occurrence, drug resistance can be classified into intrinsic or acquired (Cetin et al. 2021). For example, triple-negative breast cancer is classified under intrinsic resistance because genetic mutations exist even before therapy initiation (Mahmoud et al. 2022). Dynamic alterations of the tumor microenvironment (TME) could cause acquired drug resistance. Cross-talk between the tumor and its surrounding microenvironment is crucial for tumor progression and resistance development (Son et al. 2017). Exosomes are one of the most important mediators of such a crosstalk, secreted by both tumor and non-tumor cells. Tumor cells hijack exosomes to transfer specific cargo and promote processes like EMT, autophagy, and stemness, leading to tumor progression, angiogenesis, metastasis, and drug resistance. Indeed, it is not an exaggeration to state that exosomes deal with every aspect of tumors ( Moloudizargari et al. 2018, 2019a, b).

Exosomes facilitate drug resistance in both the cells of origin and the recipient cells. This is mainly mediated by packaging different cellular cargo and expelling them from tumor cells. First, exosomes confer drug resistance in the donor cells by exporting chemotherapeutic drugs. On the other hand, by transferring active cargo like miRNAs, proteins like ABC transporters and mitochondria, exosome could cause drug resistance in the recipient cell (Zhong et al. 2021; Abad and Lyakhovich 2022; Dong et al. 2023). For instance, studies have shown that the metabolic state of tumor cells is a key factor defining treatment response (Houshyari and Taghizadeh-Hesary 2022; Taghizadeh-Hesary et al. 2023). To overcome the problem of high energy demand, cancer cells uptake functional mitochondria from other cells, which greatly helps to repair cancer cells and escape from treatment. In this regard, Moschio et al. have shown that acute myeloid cells uptake functional mitochondria from bone marrow stromal cells leading to chemotherapy resistance induction (Moschoi et al. 2016).

Abad et al. also demonstrated that exosomes transfer mitochondria with mutated DNA from resistance triple-negative breast cancer cells to the sensitive cells and promote drug resistance. They found that inhibiting exosome release blocked the transfer of mitochondria and subsequently sensitized the cells to therapy (Abad and Lyakhovich 2022).

Searching for a solution, combination therapies became of interest to overcome resistance. Two main combination therapy approaches can be followed to combat drug resistance in cancer. The first approach is utilizing a combination of drugs aiming at different molecular targets to decrease viability of tumor cell population and prevent the development of resistance in the first place. Another approach combines drugs blocking the specific resistance mechanisms employed by the tumor cells to render them vulnerable to the conventional therapy (Saputra et al. 2018).

Exosome inhibitors are among the potential agents that have been suggested to be used in combination with chemotherapy regimens in the recent years (Datta et al. 2018). Studies have shown that these nano-vesicles could prevent drug resistance in both host and recipient cells, and re-sensitize tumor cells to conventional therapies (Steinbichler et al. 2019). In this regard, in our previous work, we showed that the co-treatment of an exosome inhibitor, GW4869, with pegylated doxorubicin significantly decreased exosome release, which led to a significant increment in AML cell death (Hekmatirad et al. 2021). In cancers like ovarian and pancreatic cancers, targeting nSMase2 by GW4869 increased chemotherapy efficacy by decreasing exosome release (Nakamura et al. 2017; Richards et al. 2017). Moreover, results of several studies have shown that agents like indomethacin, ketotifen, chloramidine, and bisindolylmaleimide-I combat drug resistance by enhancing cellular drug accumulation as a result of exosome inhibition. Therefore, exosome inhibitors are promising candidates to be used in combination regimens for treating cancer (Koch et al. 2016; Kosgodage et al. 2017; Khan et al. 2018).

Among various pathways involved in exosome biogenesis and release, the ceramide-dependent pathway seems to be a major pathway of exosome release from cells (Elsherbini and Bieberich 2018). nSMase2 is the main regulator of this pathway that hydrolyses sphingomyelin to ceramide. Put together, pharmacological inhibition of human nSMase2 could potentially reverse drug resistance by reducing exosome release (Trajkovic et al. 2008). However, issues like poor solubility, low efficacy, and unknown safety profile in human have limited the use of such inhibitors in clinic and therefore, there is a need for developing an efficient and clinically feasible inhibitor. For instance, GW4869 is the most extensively used nSMase2 inhibitor in research, but its lipophilic nature has limited its clinical use. Another known inhibitor is cambinol that despite its efficacy showed a poor pharmacokinetic and dynamic profile (Figuera-Losada et al. 2015).

Various groups have tried to address the disadvantages of the previous inhibitors, so far. In this regard, compounds, such as phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate (PDDC) and 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), have been identified, but these compounds have not yet entered the clinic due to the lack of toxicity profiles and poor pharmacokinetic properties (Rojas et al. 2018, 2019).

The development of new drug candidates requires approximately 10 years of research, and efficacy and toxicity studies. Additionally, pharmacokinetic and dynamic evaluations are required, which are costly processes. This has caused drug repositioning to gain increasing attention over the recent years. By discovering new targets and applications for FDA-approved drugs with known toxicity and pharmacokinetic profiles, researchers would be able to save a lot of time and largely reduce expenses, since these drugs may directly enter clinical trials (Tamimi and Ellis 2009). Taken this into account, our incentive of carrying out the present work was to find an efficient clinically available inhibitor of exosome release to enable accelerated investigations in cancer studies.

In this regard, Data et al. tried to identify exosome release inhibitors through a drug repositioning strategy. They performed quantitative high-throughput screen (qHTS) for 4580 active compounds. Tipifarnib, neticonazole, and ketoconazole were among the most potent candidates in their study. Subsequently, they evaluated the effect of these selected candidates on the expression of proteins (Alix, nSMase2 and Rab27a) involved in different pathways of exosome biogenesis and secretion. All three candidates affected the protein targets and decreased them. However, none of these candidates were nSMase2-specific (Trajkovic et al. 2008).

Due to the abundance of molecular pathways and targets in cancer, blind repurposing may not be an efficient strategy. Instead repurposing over a known target could potentially lead to better results (Jin and Wong 2014). Accordingly, in the current study, we screened a library of FDA-approved drugs over nSMase2, and aprepitant was the best candidate identified. We also performed the molecular dynamic simulation to validate our selection. Convergence of the RMSD plot indicated proper protein–ligand interactions. Aprepitant is a substance p/neurokinin-1 receptor (NK-1R) antagonist that is being used in chemotherapy-induced nausea and vomiting (CINV). The safety profile of this FDA-approved drug is available. Aprepitant is well tolerated and no remarkable destructive side effect has been reported, to date (Munoz et al. 2014). Unlike many molecules that have previously been investigated for nSMase2 inhibition, the IC50 of aprepitant is in the nanomolar range. Thus, aprepitant may be an outstanding candidate for nSMase2 targeting, since it has already been approved and is being used in the clinic (Berger et al. 2014). Similar to some previously found nSMase2 inhibitors like GW4869 and cambinol, aprepitant is poorly water-soluble. However, to increase its solubility, various strategies have been established and its nanoparticle forms, as well as dispersed formulations, are available (Olver et al. 2007; Yeo et al. 2020).

To validate our in silico findings, we evaluated the efficacy of aprepitant in vitro. First, the IC-50 of aprepitant was calculated using CCK-8 assay in the colorectal cancer cell line, HCT116. In the next step, we assessed nSMase2 activity following aprepitant incubation. Both cell-free and cell-based enzymatic activity assays showed significant reduction of exosome release compared with the control group. The three non-lethal aprepitant concentrations that were selected for these examinations didn’t show significant differences in their inhibition and all of them could decrease the release. We compared aprepitant potency with GW4869 and the inhibitory effect of aprepitant on nSmase2 was as potent as that of the commercially available GW4869.

Besides its antiemetic effect, aprepitant has been shown to exert an antitumor effect. Many studies in this field attributed these antitumor effects of aprepitant to its effect on NK-1R and subsequently substance p (Javid et al. 2021). Since various studies have demonstrated that the combined use of exosome inhibitors with chemotherapeutic agents improves the response cancer cells to therapy (Kosgodage et al. 2017; Khan et al. 2018; Hekmatirad et al. 2021), our hypothesis is that this effect could be partly related, at least partly, due to the inhibitory effect of aprepitant on nSMase2.

In our previous study, we showed that the combination of GW4869 with doxorubicin reduced the required dose of the drug for its cytotoxic effects on acute myeloid leukemia (AML) cells. Meanwhile, Berger et al. also observed a decrease in the required dose of doxorubicin in its combination with aprepitant. Since this effect is in line with that observed in our study and we are the first group to report aperpitant as an exosome inhibitor, we hypothesize that this effect could be also related to this newly identified function of aperpitant (Berger et al. 2014). Given that different cancer types exhibit various levels of exosome secretion as well as varying levels of exposure to the oral formulation of aprepitant, which is currently available form of the drug administered in the clinic, identifying the cancer patients who would benefit the most from combinational therapy with aprepitant remains a major open question that needs to be addressed in future works. Indeed, specific clinical trials are warranted to further assess the effects of aprepitant in the context of cancer and in combination therapies.

Conclusion

The findings of the current study indicate the capability of aprepitant to target nSMase2 and to be potentially used as an exosome inhibitor. Despite other known nSMase2 inhibitors, aprepitant has a defined pharmacokinetic and toxicity profile and is already being used in the clinical setting. Finally, designing trials on the effects of combination of aprepitant with conventional chemotherapy regimens is warranted.

Acknowledgements

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

Author 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.

Funding

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

Data availability

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

Declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Data Availability Statement

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