Oral administration of copper to rats leads to increased lymphocyte cellular DNA degradation by dietary polyphenols: implications for a cancer preventive mechanism |
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Authors: | Husain Y Khan Haseeb Zubair Mohd F Ullah Aamir Ahmad Sheikh M Hadi |
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Institution: | (1) Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, India;(2) Present address: Department of Pathobiology, University of Tennessee, Knoxville, TN 37996, USA;(3) Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; |
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Abstract: | To account for the observed anticancer properties of plant polyphenols, we have earlier proposed a mechanism which involves
the mobilization of endogenous copper ions by polyphenols leading to the generation of reactive oxygen species (ROS) that
serve as proximal DNA cleaving agents and lead to cell death. Over the last decade we have proceeded to validate our hypothesis
with considerable success. As a further confirmation of our hypothesis, in this paper we first show that oral administration
of copper to rats leads to elevated copper levels in lymphocytes. When such lymphocytes with a copper overload were isolated
and treated with polyphenols EGCG, genistein and resveratrol, an increased level of DNA breakage was observed. Further, preincubation
of lymphocytes having elevated copper levels with the membrane permeable copper chelator neocuproine, resulted in inhibition
of polyphenol induced DNA degradation. However, membrane impermeable chelator of copper bathocuproine, as well as iron and
zinc chelators were ineffective in causing such inhibition in DNA breakage, confirming the involvement of endogenous copper
in polyphenol induced cellular DNA degradation. It is well established that serum and tissue concentrations of copper are
greatly increased in various malignancies. In view of this fact, the present results further confirm our earlier findings
and strengthen our hypothesis that an important anticancer mechanism of plant polyphenols could be the mobilization of intracellular
copper leading to ROS-mediated cellular DNA breakage. In this context, it may be noted that cancer cells are under considerable
oxidative stress and increasing such stress to cytotoxic levels could be a successful anticancer approach. |
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