Coumarin-chalcone hybrid instigates DNA damage by minor groove binding and stabilizes p53 through post translational modifications

Abstract

S009-131, a coumarin-chalcone hybrid, had been shown to possess anti-proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA-PK, but not ATR, at earlier time points in order to initiate repair process. S009-131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues. Pharmacological inhibition of PIKKs abrogated S009-131 induced phosphorylation of p53 at Ser 15. DNA damage induced phosphorylation resulted in reduced proteasomal degradation of p53 by disrupting p53-MDM2 interaction. Additionally, our docking studies revealed that S009-131 might also contribute to increased cellular p53 level by occupying p53 binding pocket of MDM2. Posttranslational modifications of p53 upon S009-131 treatment led to enhanced affinity of p53 towards responsive elements (p53-RE) in the promoter regions of target genes and increased transcriptional efficiency. Together, the results suggest that S009-131 cleaves DNA through minor groove binding and eventually activates PIKKs associated DNA damage response signalling to promote stabilization and enhanced transcriptional activity of p53 through posttranslational modifications at key residues.

Unravelling the Anticancer Potential of a Square Planar Copper Complex: Toward Non-platinum Chemotherapy

“…Absorption spectroscopy is one of the most useful and effective techniques in DNA-drug interaction studies. This technique allows recognizing the existence of interactions between DNA and molecules, as well as specifying the mode of interaction by utilizing the perturbations in the spectral observation 19,42,43 . Binding of different compounds to DNA may create a strong stacking interaction between the compounds and the base pairs of the DNA, and may cause the absorbance spectrum show some degrees of hypo-or hyperchromism 43 binding to the CT-DNA 34 .…”

“…Upon DNA damage, p53 elicit a multifaceted response in the cell and it decides various important cellular processes like DNA repair, cell cycle arrest and apoptosis, thereby maintaining the genomic integrity of the cells 18,19 . Unlike, other cellular transcription factors, p 53 is known to be mutated in almost all types of cancer.…”

“…In addition, ROS generation, cell cycle analysis, DNA damage assay, apoptotic pathway analysis (caspase-3 assay) and molecular docking studies were carried out to support the results of cancer cell cytotoxicity. Since, DNA is not always the primary target of metal based anticancer molecules 35,36 , we also explore the ability of these metal complexes to bind an important cellular transcription factor protein, p53, which is an important regulator of cell growth and cell death pathways [19][20][21] . Our molecular docking results suggest that the ligand binds to the central, highly conserved DNA-binding domain region of p53 (p53DBD), that could further activate the cancer cell DNA damage, which in turn could trigger the cell signalling pathways leading to cancer cell death.…”

Ferric Ion Induction of Triggering Receptor Expressed in Myeloid Cells‐2 Expression and PI3K/Akt Signaling Pathway in Preosteoclast Cells to Promote Osteoclast Differentiation

“…Immunofluorescence assay was performed as described previously 31 . The RAW264.7 was seeded in 6-well plates at a density of 2 × 10 5 cells/well.…”

Synthesis of Structurally Diversified Benzo[c]chromene Derivatives under (An)aerobic Conditions Catalyzed by CuI

“…Coumarin is also named 2 H ‐chromen‐2‐one, which is a bicyclic oxygen‐containing heterocycle. It is reported that coumarin exists in numerous natural products , such as tanizin , anisucoumaramide , and defucogilvocarcin , and possesses good biological activities, for example, antitumor , anti‐ Escherichia coli , anticoagulation , and antifungal activities . Acenocoumarol is a noteworthy anticoagulant drug that functions as a vitamin K antagonist .…”