title: Targeting increased copper levels in diethylnitrosamine induced hepatocellular carcinoma cells in rats by epigallocatechin-3-gallate.
abstract: We have earlier elucidated a pathway for the anticancer action of plant polyphenolic compounds against malignant cells involving mobilisation of endogenous copper ions and the consequent prooxidant action. To further confirm our hypothesis in vivo, we induced hepatocellular carcinoma (HCC) in rats by diethylnitrosamine (DEN). We show that in such carcinoma cells, there is a progressive elevation in copper levels at various intervals after DEN administration. Concurrently with increasing copper levels, epigallocatechin-3-gallate (EGCG; a potent anticancer plant polyphenol found in green tea) mediated DNA breakage in malignant cells is also increased. The cell membrane permeable copper chelator neocuproine inhibited the EGCG-mediated cellular DNA degradation, whereas the membrane impermeable chelator bathocuproine was ineffective. Iron and zinc specific chelators desferoxamine mesylate and histidine, respectively, were also ineffective in inhibiting EGCG mediated DNA breakage. Through the use of specific scavengers, the mechanism of DNA breakage was determined to be mediated by reactive oxygen species. In summary, we provide an in vivo evidence of accumulating copper in hepatocellular carcinoma that is targeted by EGCG, leading to its anticancer role in a prooxidant manner. Our findings confirm a novel mechanism of anticancer activity of EGCG in particular and plant derived nutraceuticals in general.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India.
authors.forename: Mohd
authors.initials: M
authors.lastname: Farhan
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India.|Section of Radiobiology, Department of Radiology, The Biomedical Research Tower, The Ohio State University, 460W 12th Avenue, Columbus, OH, USA.
authors.forename: Asim
authors.initials: A
authors.lastname: Rizvi
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India.
authors.forename: Imrana
authors.initials: I
authors.lastname: Naseem
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India.
authors.forename: S M
authors.initials: SM
authors.lastname: Hadi
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 707 HWCRC, 4100 John R St., Detroit, 48201, MI, USA. ahmada@karmanos.org.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D002463:Cell Membrane Permeability / Q000187:drug effects; D003300:Copper / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000008:administration & dosage; D013662:Tea / Q000737:chemistry
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013662:Tea; D004052:Diethylnitrosamine; D003300:Copper; D002392:Catechin; C045651:epigallocatechin gallate
keywords: Copper; Diethylnitrosamine; EGCG; Hepatocellular carcinoma; Liver