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Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport

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Summary

Targeting tumor metabolic vulnerabilities such as “glutamine addiction” has become an attractive approach for the discovery of novel antitumor agents. Among various mechanisms explored, SLC1A5, a membrane transporter that plays an important role in glutamine cellular uptake, represents a viable target to interfere with tumor’s ability to acquire critical nutrients during proliferation. In the present study, a stably transfected HEK293 cell line with human SLC1A5 (HEK293-SLC1A5) was established for the screening and identification of small molecule SLC1A5 inhibitors. This in vitro system, in conjunction with direct measurement of SLC1A5-mediated L-glutamine-2,3,3,4,4-D5 (substrate) uptake, was practical and efficient in ensuring the specificity of SLC1A5 inhibition. Among a group of diverse compounds tested, mianserin (a tetracyclic antidepressant) demonstrated a marked inhibition of SLC1A5-mediated glutamine uptake. Subsequent investigations using SW480 cells demonstrated that mianserin was capable of inhibiting SW480 tumor growth both in vitro and in vivo, and the in vivo antitumor efficacy was correlated to the reduction of glutamine concentrations in tumor tissues. Computational analysis revealed that hydrophobic interactions between SLC1A5 and its inhibitors could be a critical factor in drug design. Taken together, the current findings confirmed the feasibility of targeting SLC1A5-mediated glutamine uptake as a novel approach for antitumor intervention. It is anticipated that structural insights obtained based on homology modeling would lead to the discovery of more potent and specific SLC1A5 inhibitors for clinical development.

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Data Availability

The data presented in this study are available in the paper and Supplementary Information.

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Acknowledgements

The authors were grateful for the technical assistance provided by Dr. Fanyi Meng during the establishment of the SW480 tumor xenograft model as well as database search and analysis.

Funding

This research was supported by the National Natural Science Foundation of China (No. 82173880).

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Author notes

  1. Zelin Duan and Zhiyun Zhou contributed equally to this work.

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Zelin Duan, Zhiyun Zhou, Feifei Lu, Yawen Zhang, Xvqin Guo, Chunshan Gui & Hongjian Zhang

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Contributions

Z.D. and Z.Z. participated in the design and conduct of in vitro and in vivo experiments in addition to data analysis and manuscript drafting and editing. F.L., Y.Z. and X.G. contributed to the establishment of in vitro cell models as well as in vivo xenograft models. C.G. was instrumental in computational analysis and manuscript drafting. H.Z. was involved in conceptualization of the studies and manuscript drafting, editing and finalization.

Corresponding author

Correspondence to Hongjian Zhang.

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Ethics approval

All experimental procedures were performed in accordance with the NIH guidelines for Care and Use of Laboratory Animals; all procedures and protocols were approved by the Institutional Animal Care and Use Committee at Soochow University (#202107A0121). Patents A patent application on a method for screening of SLC1A5 inhibitors and mianserin’s use as antitumor agent has been filed with the China National Intellectual Property Administration (Application number: CN202111328929.3).

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The authors declare no potential conflicts of interest during the study and preparation of the manuscript.

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Duan, Z., Zhou, Z., Lu, F. et al. Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport. Invest New Drugs 40, 977–989 (2022). https://doi.org/10.1007/s10637-022-01284-w

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