2‐(6‐Hydroxyhexylthio)‐5,8‐dimethoxy‐1,4‐naphthoquinone Induces Apoptosis through ROS‐Mediated MAPK, STAT3, and NF‐κB Signalling Pathways in Lung Cancer A549 Cells

Abstract

Two novel compounds, 2-(2-hydroxyethylthio)-5,8-dimethoxy-1,4-naphthoquinone (HEDMNQ) and 2-(6-hydroxyhexylthio)-5,8-dimethoxy-1,4-naphthoquinone (HHDMNQ), were synthesized to investigate the kill effects and mechanism of 1,4-naphthoquinone derivatives in lung cancer cells. The results of the CCK-8 assay showed that HEDMNQ and HHDMNQ had significant cytotoxic effects on A549, NCI-H23, and NCI-H460 NSCLC cells. Flow cytometry and western blot results indicated that HHDMNQ induced A549 cell cycle arrest at the G2/M phase by decreasing the expression levels of cyclin-dependent kinase 1/2 and cyclin B1. Fluorescence microscopy and flow cytometry results indicated that HHDMNQ could induce A549 cell apoptosis, and western blot analysis showed that HHDMNQ induced apoptosis through regulating the mitochondria pathway, as well as the MAPK, STAT3, and NF-κB signalling pathways. Flow cytometry results showed that intracellular reactive oxygen species (ROS) levels were increased after HHDMNQ treatment, and western blot showed that ROS could modulate the intrinsic pathway and MAPK, STAT3, and NF-κB signalling pathways. These effects were blocked by the ROS inhibitor N-acetyl-L-cysteine in A549 cells. Our findings suggest that compared with HEDMNQ, HHDMNQ had the stronger ability to inhibit the cell viability of lung cancer cells and induce apoptosis by regulating the ROS-mediated intrinsic pathway and MAPK/STAT3/NF-κB signalling pathways. Thus, HHDMNQ might be a potential antitumour compound for treating lung cancer.

Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2

“…When cancerous cells were incubated with the most potent compounds, authors reported the increased ROS production by liver cancer cells in vitro [ 45 ]. Further studies identified 2-(4-methoxyphenylthio)-5,8-dimethoxy-1,4-naphthoquinone as a powerful ROS-inducing anticancer compound that exerts anticancer activity by interfering with MAPK and STAT3 signaling pathways [ 46 ]. The antiproliferative compound was able to decrease the phosphorylation of extracellular signal-regulated kinase (ERK) leading to the induction of apoptosis events in human gastric cancer cell lines.…”

Targeted therapy for non‐small‐cell lung cancer: New insights into regulated cell death combined with immunotherapy

“…57 the MAPK/STAT3/NF-κB signaling pathway, accordingly promoting the activation of caspase-3 and, subsequently, cell apoptosis. 60 As previously mentioned, the anticancer properties of TPL…”

“…It also reduced ROS levels and arrested the cell cycle in the G2/M stage. Notably, HHDMNQ increased the Bax/Bcl‐2 ratio by decreasing ROS levels and enacting the MAPK/STAT3/NF‐κB signaling pathway, accordingly promoting the activation of caspase‐3 and, subsequently, cell apoptosis 60 . As previously mentioned, the anticancer properties of TPL ( 1 ) have been extensively analyzed 61 .…”

C-Ring Oxidized Estrone Acetate Derivatives: Assessment of Antiproliferative Activities and Docking Studies

“…Thus, the size of the group at C9 seems to be important for estrogenic and cytotoxic activities. Concerning the cell cycle effects of these compounds, some studies showed that several steroids [59,60] as well as non-steroids [61][62][63] lead to cell cycle arrest. In this context and as an example, 11α-substituted 2-methoxyestradiol derivatives led to a cell cycle arrest at G 2 /M and demonstrated an important antiestrogenic effect [5].…”