Structure of Some Green Tea Catechins and the Availability of Intracellular Copper Influence Their Ability to Cause Selective Oxidative DNA Damage in Malignant Cells

Abstract

The possible roles of elevated endogenous copper levels in malignant cells are becoming increasingly understood at a greater depth. Our laboratory has previously demonstrated that tea catechins have the ability to mobilize endogenous copper and undergo a Fenton-like reaction that can selectively damage cancer cells. In this communication, by using a diverse panel of malignant cell lines, we demonstrate that the ability of the catechin family [(−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin (EC), and (+)-catechin (C)] to induce apoptosis is dependent on their structure. We further confirm that reactive oxygen species (ROS) are the terminal effectors causing copper-mediated DNA damage. Our studies demonstrate the role of cellular copper transporters CTR1 and ATP7A in the survival dynamics of malignant cells post-EGCG exposure. The results, when considered together with our previous studies, highlight the critical role that copper dynamics and mobilization plays in cancer cells and paves the way for a better understanding of catechins as nutraceutical supplements for malignancies.

Understanding the Prooxidant Action of Plant Polyphenols in the Cellular Microenvironment of Malignant Cells: Role of Copper and Therapeutic Implications

“…A large proportion of the total polyphenolic molecules contain several hydroxyl groups, which subsequently undergo sulfatation, glucuronidation and methylation. It is important to point out at this juncture, that hydroxyl groups and their relative positions within the molecule are shown to have fundamental importance in the copper based ROS mediated mechanism that we have proposed ( Pryor, 1988 ; Cao et al, 1997 ; Farhan et al, 2015a ; Farhan et al, 2016 ; Arif et al, 2018 ; Farhan et al, 2022 ). Secondly, it is estimated that the intestinal absorption of polyphenols as such tends to range between 5 and 10% of the total polyphenolic content.…”

“…These beneficial effects are attributed to plants derived polyphenolic compounds. The polyphenol uptake can be the result of drinking green tea (catechins) ( Farhan et al, 2022 ), consumption of large amounts of soybeans products (genistein) ( Ullah et al, 2011a ), berries (anthocyanins), red grapes and red wine (resveratrol), turmeric (curcumin), parsley (apigenin), and onion (quercetin) ( Khan et al, 2012 ). The results of recent studies indicate, that these compounds serve as therapeutic molecules, thatcan aid both prevention and treatment of cancer.…”

“…Recently, we showed that culturing normal breast epithelial cells (MCF10A) in a medium enriched with copper sensitizes these cells to polyphenol mediated growth inhibition. This sensitization also leads to an increased expression of both CTR1 and ATP7A (membrane bound copper transporters) ( Farhan et al, 2022 ). The over-expression led to further accumulation of more copper in such cells ( Brewer, 2005 ; Farhan et al, 2022 ).…”

“…This sensitization also leads to an increased expression of both CTR1 and ATP7A (membrane bound copper transporters) ( Farhan et al, 2022 ). The over-expression led to further accumulation of more copper in such cells ( Brewer, 2005 ; Farhan et al, 2022 ). siRNA mediated silencing of the copper-transporter CTR1 led to a reduction in the sensitivity of these cells to EGCG mediated cell death.…”

“…siRNA mediated silencing of the copper-transporter CTR1 led to a reduction in the sensitivity of these cells to EGCG mediated cell death. ( Farhan et al, 2022 ).…”