Thymoquinone, artemisinin, and thymol attenuate proliferation of lung cancer cells as Sphingosine kinase 1 inhibitors

• Published in: Biomedicine & pharmacotherapy Vol. 177; p. 117123
• Main Authors: Shakeel, Ilma, Haider, Shaista, Khan, Shama, Ahmed, Shahbaz, Hussain, Afzal, Alajmi, Mohamed F., Chakrabarty, Anindita, Afzal, Mohammad, Imtaiyaz Hassan, Md
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-08-2024; Elsevier
• Subjects: Anticancer therapy; Apoptosis; Cell signaling; Cytotoxicity; Drug discovery; Drug targeting; Kinase inhibitors; Natural inhibitors; Sphingosine kinase 1; HBA; Cytotoxicity; CIB1; Cell signaling; S1P; Rg; SphK1; MD; Drug targeting; NSCLC; HIF; MM/GBSA; RMSF; RMSD; Sphingosine kinase 1; Natural inhibitors; PCA; AR; DCCM; TM; SASA; Drug discovery; Kinase inhibitors; Anticancer therapy; TQ; Apoptosis
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117123

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non–small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.
[Display omitted]
•SphK1 is an attractive drug target for cancer therapy and thus targeted for the drug development.•We have identified TQ, AR, and TM as potent inhibitors of SphK1.•Docking and MD simulation studies suggested a strong binding and the formation of a stable protein-ligand complex.•TQ, AR, and TM significantly inhibit the activity of SphK1 with significant IC50 values.•TQ shows cytotoxic effect on H1299 and A549, which is linked to the mitochondrial ROS generation.