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Unraveling the molecular mechanism of l-menthol against cervical cancer based on network pharmacology, molecular docking and in vitro analysis

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Abstract

Cervical cancer is a major cause of gynecological related mortalities in developing countries. Cisplatin, a potent chemotherapeutic agent used for treating advanced cervical cancer exhibits side effects and resistance development. The current study was aimed to investigate the repurposing of l-menthol as a potential therapeutic drug against cervical cancer. L-menthol was predicted to be non-toxic with good pharmacokinetic properties based on SwissADME and pkCSM analysis. Subsequently, 543 and 1664 targets of l-menthol and cervical cancer were identified using STITCH, BATMAN-TCM, PharmMapper and CTD databases. STRING and Cytoscape analysis of the merged protein–protein interaction network revealed 107 core targets of l- menthol against cervical cancer. M-CODE identified highly connected clusters between the core targets which through KEGG analysis were found to be enriched in pathways related to apoptosis and adherence junctions. Molecular docking showed that l- menthol targeted E6, E6AP and E7 onco-proteins of HPV that interact and inactivate TP53 and Rb1 in cervical cancer, respectively. Molecular docking also showed good binding affinity of l-menthol toward proteins associated with apoptosis and migration. Molecular dynamics simulation confirmed stability of the docked complexes. In vitro analysis confirmed that l-menthol was cytotoxic towards cervical cancer CaSki cells and altered expression of TP53, Rb1, CDKN1A, E2F1, NFKB1, Akt-1, caspase-3, CDH1 and MMP-2 genes identified through network pharmacology approach.

Graphical abstract

Schematic representation of the work flow depicting the potential of l-menthol to target cervical cancer.

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The data generated and analyzed for the study has been included in the article and its associated supplementary information files.

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Acknowledgements

Harsimran Sidhu acknowledges research fellowship from Indian Council of Medical Research, New Delhi, India.

Funding

This work was supported by University Grants Commission, New Delhi, India {F. No. 43–72/2014 (SR)}.

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Authors and Affiliations

  1. Department of Biotechnology, Panjab University, Basic Medical Science (Block-I), Sector-25, Chandigarh, 160014, India

    Harsimran Sidhu, Lalit Kumar Gautam & Neena Capalash

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  2. Lalit Kumar Gautam
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HS: Conceptualization, investigation, methodology, validation, formal analysis, writing original draft, writing-review and editing, visualization. LKG: Methodology, formal analysis, writing of molecular dynamics simulation by GROMACS. NC: Conceptualization, validation, resources, writing-review and editing, visualization, project administration, supervision, funding acquisition.

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Correspondence to Neena Capalash.

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Sidhu, H., Gautam, L.K. & Capalash, N. Unraveling the molecular mechanism of l-menthol against cervical cancer based on network pharmacology, molecular docking and in vitro analysis. Mol Divers 27, 323–340 (2023). https://doi.org/10.1007/s11030-022-10429-1

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