title: Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism.
abstract: Ferulic acid (FA) is a plant polyphenol showing diverse therapeutic effects against cancer, diabetes, cardiovascular and neurodegenerative diseases. FA is a known antioxidant at lower concentrations, however at higher concentrations or in the presence of metal ions such as copper, it may act as a pro-oxidant. It has been reported that copper levels are significantly raised in different malignancies. Cancer cells are under increased oxidative stress as compared to normal cells. Certain therapeutic substances like polyphenols can further increase this oxidative stress and kill cancer cells without affecting the proliferation of normal cells. Through various in vitro experiments we have shown that the pro-oxidant properties of FA are enhanced in the presence of copper. Comet assay demonstrated the ability of FA to cause oxidative DNA breakage in human peripheral lymphocytes which was ameliorated by specific copper-chelating agent such as neocuproine and scavengers of ROS. This suggested the mobilization of endogenous copper in ROS generation and consequent DNA damage. These results were further validated through cytotoxicity experiments involving different cell lines. Thus, we conclude that such a pro-oxidant mechanism involving endogenous copper better explains the anticancer activities of FA. This would be an alternate non-enzymatic, and copper-mediated pathway for the cytotoxic activities of FA where it can selectively target cancer cells with elevated levels of copper and ROS.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India.
authors.forename: Tarique
authors.initials: T
authors.lastname: Sarwar
authors.affiliation: Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, Central University, New Delhi 110025, India.
authors.forename: Md
authors.initials: M
authors.lastname: Zafaryab
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India.
authors.forename: Mohammed Amir
authors.initials: MA
authors.lastname: Husain
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India.
authors.forename: Hassan Mubarak
authors.initials: HM
authors.lastname: Ishqi
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India.
authors.forename: Sayeed Ur
authors.initials: SU
authors.lastname: Rehman
authors.affiliation: Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, Central University, New Delhi 110025, India.
authors.forename: M Moshahid Alam
authors.initials: MM
authors.lastname: Rizvi
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India. Electronic address: tabish.bcmlab@gmail.com.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tabish
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D020552:Comet Assay; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D003412:Cricetulus; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002614:Chelating Agents; D003373:Coumaric Acids; D016166:Free Radical Scavengers; D016877:Oxidants; D017382:Reactive Oxygen Species; D003300:Copper; C004999:ferulic acid
keywords: Copper; Cytotoxicity; DNA breakage; Ferulic acid; Pro-oxidant; ROS