Exploring the Molecular Mechanisms of Senegenin in Lung Cancer via PI3K/AKT/mTOR Pathway and Computational Docking Studies

Background

Lung cancer is a pervasive global malignancy that stands as a foremost cause of cancer-induced fatalities, defined by its heightened intratumor heterogeneity and the intricate nature of its cellular pathology. It accounts for an estimated 25% of all global cancer-related fatalities, making it the primary cause of cancer deaths despite the development of clinical treatments.

Objectives

The present work was designed to evaluate the anticancer mechanisms of senegenin against lung cancer A549 cells using an in vitro and in silico approach.

Materials and Methods

The MTT test was utilized to examine the growth of lung cancer A549 cells treated with senegenin at different concentrations (5-30 μM). The incidences of apoptotic cell deaths in the senegenin-treated A549 cells were evaluated using a dual staining method. The levels of PI3K, Akt, and mTOR in the control and senegenin-treated A549 cells were evaluated with appropriate assay kits. The interactions between the senegenin and the PI3K, Akt, and mTOR were evaluated using Autodock vina and visualized using Discovery Studio Visualizer (DSV). The drug-likeness and toxicity profile of senegenin were predicted using ProTox v3.0.

Results

The findings of the MTT assay indicated that senegenin treatment (5-30 μM) significantly reduced the A549 cell viability in a dose-dependent dependently. The dual staining results indicated the increased presence of apoptotic incidences in the senegenin-treated A549 cells. The levels of PI3K, Akt, and mTOR were markedly decreased in the A549 cells after treatment with senegenin. The molecular docking analysis revealed that senegenin exhibited strong interactions with the key components of the PI3K/Akt/mTOR signaling pathway such as PI3K (Binding Affinity (BA) = -7.4 kcal/mol; RMSD = 2.263Å), AKT (BA = -9.0 kcal/mol; RMSD = 2.493Å), and mTOR (BA = -7.4 kcal/mol; RMSD = 2.613Å).

Conclusion

The current findings suggest that senegenin interacts with PI3K, Akt, and mTOR and may potentially inhibit downstream signaling events associated with cell growth, proliferation, and survival in lung cancer progression. The docking results supported the hypothesis that senegenin could act as a multi-target inhibitor to modulate the oncogenic PI3K/Akt/mTOR signaling pathway. Consequently, it may be a promising anticancer candidate for treating lung cancer.