Coumarin Derivatives Exert Anti-Lung Cancer Activity by Inhibition of Epithelial–Mesenchymal Transition and Migration in A549 Cells

Abstract

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC50 = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC50 value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines.

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition

“…Previous reports revealed that the activation of EMT process renders cytoskeleton remolding of cancer cells followed by the acquirement of new characteristics including the enhanced metastasis and invasion ( de Araújo et al, 2022 ; Meng et al, 2022 ). Therefore, in this study, wound-healing assay and invasion assay were conducted to examine cell migration and invasion and the data displayed that both migration ( Figure 3A ) and invasive ability ( Figure 3B ) of A549 cells treated with low-dose (0.5 μg/ml) cisplatin were increased compared with that of controls.…”

Therapeutic effects of medicinal plants and their constituents on lung cancer, in vitro, in vivo and clinical evidence

“…90 Coumarin derivatives (12 μM) significantly decreased the migration of IL-1β-stimulated cells and IL-1β levels and inhibited F-actin reorganization in A549 cell lines. 91 An earlier study found that administration of coumarin-based benzopyranone derivatives (20 μM) up-regulated the apoptotic pathway via Bax protein expression but down-regulated Bcl-2 protein expression in human lung (A549) cancer cells. 92 Based on the above findings, further investigation in F. persica and its main constituent coumarin as a possible treatment for lung cancer via the inhibition of cyclins and CDK, their reducing effects on cancer cell migration and metastasis mediated by cytokines such as IL-1β, oxidative marker production, cell viability and cytotoxicity warrant further investigation.…”

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches

“…Among the tyrosinase inhibitors, several authors have described the role of secondary plant metabolites, especially phenolic derivatives [ 24 , 25 , 26 ], including coumarins or 2 H -1-benzopyran-2-one, which are chemically characterized by the presence of a benzene ring fused to an α -pyrone [ 27 ]. This class of secondary metabolites arouses great interest in the academic community due to their vast pharmacological applications [ 28 , 29 , 30 , 31 ], such as their antitumor activities toward various cancer lineages [ 32 , 33 , 34 , 35 ], including human colon cancer (HCT-116) and human adenocarcinoma (HeLa) [ 36 ], and also their properties as anti-melasma agents and tyrosinase inhibitors [ 37 , 38 ]. As some examples ( Figure 1 ), we can highlight the studies performed by Pintus et al and Matos et al, who synthesized a series of heteroarylcoumarins and evaluated their inhibitory activities on mushroom tyrosinase, identifying compounds 1 and 2 as the most promising tyrosinase inhibitors [ 39 , 40 , 41 ].…”