Fenretinide induces apoptosis and synergises the apoptosis inducing effect of gemcitabine through inhibition of key signalling molecules involved in A549 cell survival in in silico and in vitro analyses.

Al-Bustany, H. A., Muhammad, H. A., Chawsheen, M. A. and Dash, P. R. (2023) Fenretinide induces apoptosis and synergises the apoptosis inducing effect of gemcitabine through inhibition of key signalling molecules involved in A549 cell survival in in silico and in vitro analyses. Cellular Signalling, 111. 110885. ISSN 0898-6568 doi: 10.1016/j.cellsig.2023.110885

Abstract/Summary

Fenretinide is a synthetic retinoid compound, which induces apoptosis via generating reactive oxygen species (ROS) and modulating PI3K/Akt/mTOR signalling pathway. We hypothesise that fenretinide's mechanism of action in triggering apoptosis may involve other targets, beside mTOR signalling pathway and it may augment apoptosis inducing effects of chemotherapeutic drugs in lung cancer. Time-lapse microscopy and Western blotting were used to evaluate apoptosis and apoptotic marker cleaved-Caspase 3 in A549 cells. Relative levels of protein phosphorylation and ROS were quantified by Human Phospho-Kinase Array Kit and CellROX® Green Reagent, respectively. Docking and simulation analyses of proteins and fenretinide interactions were identified and visualised by Discovery Studio Visualizer and AutoDock Vina software. Our results showed that fenretinide induced apoptosis in a dose dependant manner and combinations of fenretinide (5 μg/mL) and gemcitabine (1, 2, 4, 8 and 16 μg/mL) synergistically enhanced apoptosis in A549 cells. Fenretinide caused significant increase of cleaved-Caspase 3, de-phosphorylated p-S473 of Akt and failed to inhibit mTORC1 downstream targets. In silico results revealed that Akt required the lowest energy (-10.2 kcal/mol) to interact with fenretinide in comparison with other proteins. In conclusion, Akt may be exploited as a good target for induction of apoptosis in A549 cells and fenretinide has great potentials to fulfil this task. The mechanism by which fenretinide boosts the apoptosis inducing effects of gemcitabine, which is likely expected to be via inhibiting mTORC2 downstream targets. However, docking investigation revealed that fenretinide lacks specificity as it may also interact with several secondary targets beside Akt.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/113450
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Uncontrolled Keywords	Fenretinide, Docking, Akt, Gemcitabine, Lung cancer, AutoDock Vina
Publisher	Elsevier
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