A synthetic coumarin derivative (4‐flourophenylacetamide‐acetyl coumarin) impedes cell cycle at G0/G1 stage, induces apoptosis, and inhibits metastasis via ROS‐mediated p53 and AKT signaling pathways in A549 cells

Abstract

New chemotherapeutic agents with minimum side effects are indispensable to treat non-small-cell lung cancer (NSCLC) since the mortality rate of patients suffering from NSCLC remains high despite receiving conventional medication. In our previous study, many coumarin derivatives were screened for their anticancer properties in A549, an in vitro NSCLC model. One of these, 4-flourophenylacetamideacetyl coumarin (4-FPAC), induced cytotoxicity at a concentration as low as 0.16 nM. Herein, initially, the cytotoxic potential of 4-FPAC was tested on a noncancerous cell line NIH3T3 and was found safe at the selected dose of 0.16 nM. Further, we investigated the mechanism by which 4-FPAC induced cytotoxicity and arrested the progression of cell cycle as well as metastasis in A549. Results of ethidium bromide/ acridine orange (EtBr/AO), 4,6-diamidino-2-phenylindole, comet, and lactate dehydrogenase assays revealed that 4-FPAC caused cytotoxicity via reactive oxygen species-induced p53-mediated mechanism, which involves both extrinsic and intrinsic pathways of apoptosis. Dichlorodihydrofluorescein diacetate, rhodamine 123, and AO staining confirmed the involvement of both mitochondria and lysosome in inducing apoptosis. However, flow cytometric analysis revealed that it causes cell cycle arrest at the G0/G1 phase by modulating p21, CDK2, and CDK4 expression. Aggregation, soft-agar, clonogenic, and scratch assays as well as gene expression analysis collectively confirmed that 4-FPAC minimizes the metastatic property of A549 by downregulating Snail, matrix metalloproteinase 9, and interleukin-8. Additional studies reaffirmed the above findings and substantiated the role of PI3K/ AKT in achieving them. The cell-type-specific selective cytostatic and antimetastatic properties shown by 4-FPAC indicate its potential to emerge as a drug of choice against NSCLC in the future.

LncRNA WT1-AS/miR-494-3p Regulates Cell Proliferation, Apoptosis, Migration and Invasion via PTEN/PI3K/AKT Signaling Pathway in Non-Small Cell Lung Cancer

“…5 Recent studies have shown that the activation of PI3K/AKT signaling pathway can modulate proliferation, apoptosis, cycle arrest, migration and invasion of lung cancer cells. 6,7 Phosphatase and tensin homologue deleted on chromosome ten (PTEN), a lipid phosphatase that functions as a tumor suppressor, has been widely affirmed to suppress tumor progression through PI3K/AKT signaling pathway. 8 MicroRNAs (miRNAs) are endogenous non-coding small RNA molecules, which mediate the gene expression at the post-transcriptional level by binding to mRNAs, thus participating in the regulation of various biological processes.…”

Fragment‐type 4‐azolylcoumarin derivatives with anticancer properties

“…Anticancer properties of various coumarin derivatives were comprehensively examined and it is clear that they can inhibit the growth, proliferation, and metastasis of cancer cells (Figure 1). [ 18–30 ]…”

Coumarin Derivative N6 as a Novel anti-hantavirus Infection Agent Targeting AKT

“…Increasing evidence showed that phosphoinositide kinases played a momentous role in mediating viral infections ( Burke, 2018 ), and the coumarin derivatives exhibited a tremendous inhibitory activity toward the phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) pathways ( Ma and Liu, 2017 ; Umar et al, 2020 ). We also explored the possible role of N6 targeting the PI3K/Akt signaling pathway during HTNV infection.…”