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Investigating the chemo-preventive role of noscapine in lung carcinoma via therapeutic targeting of human aurora kinase B

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Abstract

Lung carcinoma is the major contributor to global cancer incidence and one of the leading causes of cancer-related mortality worldwide. Irregularities in signal transduction events, genetic alterations, and mutated regulatory genes trigger cancer development and progression. Selective targeting of molecular modulators has substantially revolutionized cancer treatment strategies with improvised efficacy. The aurora kinase B (AURKB) is a critical component of the chromosomal passenger complex and is primarily involved in lung cancer pathogenesis. Since AURKB is an important therapeutic target, the design and development of its potential inhibitors are attractive strategies. In this study, noscapine was selected and validated as a possible inhibitor of AURKB using integrated computational, spectroscopic, and cell-based assays. Molecular docking analysis showed noscapine occupies the substrate-binding pocket of AURKB with strong binding affinity. Subsequently, MD simulation studies confirmed the formation of a stable AURKB-noscapine complex with non-significant alteration in various trajectories, including RMSD, RMSF, Rg, and SASA. These findings were further experimentally validated through fluorescence binding studies. In addition, dose-dependent noscapine treatment significantly attenuated recombinant AURKB activity with an IC50 value of 26.6 µM. Cell viability studies conducted on A549 cells and HEK293 cells revealed significant cytotoxic features of noscapine on A549 cells. Furthermore, Annexin-PI staining validated that noscapine triggered apoptosis in lung cancer cells, possibly via an intrinsic pathway. Our findings indicate that noscapine-based AURKB inhibition can be implicated as a potential therapeutic strategy in lung cancer treatment and can also provide a novel scaffold for developing next-generation AURKB-specific inhibitors.

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Data availability

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

Abbreviations

ATP:

Adenosine-tri phosphate

AURKB:

Aurora kinase B

A549:

DAPI

4',6-diamidino-2-phenylindole:

Human alveolar basal epithelial cells

HEK293:

Human embryonic kidney cells

DMEM:

Dulbecco's modified eagle medium

EMT:

Epithelial to mesenchymal transition

FBS:

Fetal bovine serum

IBs:

Inclusion bodies

IC50 :

Half-maximal inhibitory concentration

Ni–NTA:

Nickel-nitrilotriacetic acid chromatography

MD:

Molecular dynamics

µM:

Micromolar

mM:

Millimolar

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide

PASS:

Prediction of activity spectra for substances

PI:

Propidium iodide

Rg :

Radius of gyration

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square frequency

SASA:

Solvent accessible surface area

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Acknowledgements

SN and MIH thank the Department of Health and Research, Government of India, for the award of the Young Scientist Fellowship (Grant No. R.12014/60/2022-HR). AH acknowledge generous support to the Researchers Supporting Project Number (RSPD2024R980), King Saud University, Riyadh, Saudi Arabia.

Funding

This work is supported by grants from the Department of Health and Research, Government of India (Grant No.R.12014/60/2022-HR). Research Supporting Project Number (RSPD2024R980) King Saud University. 

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S.N., A.A., and M.I.H. designed the study. S.N., K.U.I., A.C., M.Y., and A.R. carried out experiments and wrote the manuscript, S.N., K.U.I., A.C., M.Y., A.R., M.A.A., and A.H. contributed to analyzing the data. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Md Imtaiyaz Hassan.

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Noor, S., Choudhury, A., Islam, K.U. et al. Investigating the chemo-preventive role of noscapine in lung carcinoma via therapeutic targeting of human aurora kinase B. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-05036-7

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