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Copper-redox cycling by coumarin-di(2-picolyl)amine hybrid molecule leads to ROS-mediated DNA damage and apoptosis: A mechanism for cancer chemoprevention. | LitMetric

Copper-redox cycling by coumarin-di(2-picolyl)amine hybrid molecule leads to ROS-mediated DNA damage and apoptosis: A mechanism for cancer chemoprevention.

Chem Biol Interact

Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India. Electronic address:

Published: June 2018

AI Article Synopsis

  • - Coumarin is a bioactive compound found in plants that has been shown to have anticancer properties, with its effectiveness relying on its specific chemical structure and interactions.
  • - A new hybrid molecule (ligand-L) was created that binds to copper ions and can generate reactive oxygen species (ROS), which are harmful to cancer cells, specifically in a model mimicking cancer-like conditions through increased copper levels.
  • - The study found that ligand-L interacts with copper in cancer cells, causing oxidative stress and DNA damage, ultimately leading to cell death, and suggests that targeting copper could be a promising approach in cancer therapy.

Article Abstract

Coumarin is an important bioactive pharmacophore. It is found in plants as a secondary metabolite and exhibits diverse pharmacological properties including anticancer effects against different malignancies. Therapeutic efficacy of coumarin derivatives depends on the pattern of substitution and conjugation with different moieties. Cancer cells contain elevated copper as compared to normal cells that plays a role in angiogenesis. Thus, targeting copper in malignant cells via copper chelators can serve as an attractive targeted anticancer strategy. Our previous efforts led to the synthesis of di(2-picolyl)amine-3(bromoacetyl)coumarin hybrid molecule (ligand-L) endowed with DNA/Cu(II) binding properties, and ROS generation ability in the presence of copper ions. In the present study, we aimed to validate copper-dependent cytotoxic action of ligand-L against malignant cells. For this, we used a cellular model system of copper (Cu) overloaded lymphocytes (CuOLs) to simulate malignancy-like condition. In CuOLs, lipid peroxidation/protein carbonylation, ROS generation, DNA fragmentation and apoptosis were investigated in the presence of ligand-L. Results showed that ligand-L-Cu(II) interaction leads to ROS generation, lipid peroxidation/protein carbonylation (oxidative stress parameters), DNA damage, up-regulation of p53 and mitochondrial-mediated apoptosis in treated lymphocytes. Further, pre-incubation with neocuproine (membrane permeable copper chelator) and ROS scavengers attenuated the DNA damage and apoptosis. These results suggest that cellular copper acts as molecular target for ligand-L to propagate redox cycling and generation of ROS via Fenton-like reaction leading to DNA damage and apoptosis. Further, we showed that ligand-L targets elevated copper in breast cancer MCF-7 and colon cancer HCT116 cells leading to a pro-oxidant inhibition of proliferation of cancer cells. In conclusion, we propose copper-dependent ROS-mediated mechanism for the cytotoxic action of ligand-L in malignant cells. Thus, targeting elevated copper represents an effective therapeutic strategy for selective cytotoxicity against malignant cells.

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Source
http://dx.doi.org/10.1016/j.cbi.2018.05.010DOI Listing

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