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Evodiamine potentiates cisplatin-induced cell death and overcomes cisplatin resistance in non-small-cell lung cancer by targeting SOX9-β‐catenin axis

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Abstract

Background

In recent decades, phytotherapy has remained as a key therapeutic option for the treatment of various cancers. Evodiamine, an excellent phytocompound from Evodia fructus, exerts anticancer activity in several cancers by modulating drug resistance. However, the role of evodiamine in cisplatin-resistant NSCLC cells is not clear till now. Therefore, we have used evodiamine as a chemosensitizer to overcome cisplatin resistance in NSCLC.

Methods

Here, we looked into SOX9 expression and how it affects the cisplatin sensitivity of cisplatin-resistant NSCLC cells. MTT and clonogenic assays were performed to check the cell proliferation. AO/EtBr and DAPI staining, ROS measurement assay, transfection, Western blot analysis, RT-PCR, Scratch & invasion, and comet assay were done to check the role of evodiamine in cisplatin-resistant NSCLC cells.

Results

SOX9 levels were observed to be higher in cisplatin-resistant A549 (A549CR) and NCI-H522 (NCI-H522CR) compared to parental A549 and NCI-H522. It was found that SOX9 promotes cisplatin resistance by regulating β-catenin. Depletion of SOX9 restores cisplatin sensitivity by decreasing cell proliferation and cell migration and inducing apoptosis in A549CR and NCI-H522CR. After evodiamine treatment, it was revealed that evodiamine increases cisplatin-induced cytotoxicity in A549CR and NCI-H522CR cells through increasing intracellular ROS generation. The combination of both drugs also significantly inhibited cell migration by inhibiting epithelial to mesenchymal transition (EMT). Mechanistic investigation revealed that evodiamine resensitizes cisplatin-resistant cells toward cisplatin by decreasing the expression of SOX9 and β-catenin.

Conclusion

The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

The authors are grateful to National Institute of Technology, Rourkela, Odisha, India, for providing laboratory and equipment facilities to carry out the research.

Funding

MP’s research was funded by grants from the Department of Science and Technology, Science and Engineering Research Board (DST, SERB), New Delhi, India (Grant Number: ECR/2016/000792), and the Department of Science and Technology, Odisha, India (Grant no-1201). SB was supported by a grant from the University Grant Commission (UGC), New Delhi, India (Grant Number: 997/(CSIR-UGC NET JUNE 2019)).

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Authors and Affiliations

  1. Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha,, 769008, India

    Munmun Panda, Stuti Biswal & Bijesh K. Biswal

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  1. Munmun Panda
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  2. Stuti Biswal
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Contributions

MP: conceptualization, methodology, data curation, formal analysis, and writing–original draft, BKB: investigation and supervision, SB: formal analysis and writing–review and editing.

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Correspondence to Bijesh K. Biswal.

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Panda, M., Biswal, S. & Biswal, B.K. Evodiamine potentiates cisplatin-induced cell death and overcomes cisplatin resistance in non-small-cell lung cancer by targeting SOX9-β‐catenin axis. Mol Biol Rep 51, 523 (2024). https://doi.org/10.1007/s11033-024-09477-7

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