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

Abstract

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, driver 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 key component of the chromosomal passenger complex and is primarily involved in lung cancer pathogenesis. Since AURKB is an attractive therapeutic target, the design and development of its potential inhibitors is an attractive strategy. In this study, noscapine, a benzylisoquinoline alkaloid, was selected and validated as a potential 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 tandem 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.