title: Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants.
abstract: Plant-derived dietary antioxidants have attracted considerable interest in recent past for their chemopreventive and cancer therapeutic abilities in animal models. Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive. Although several mechanisms have been suggested for the chemopreventive and anticancer activity of TQ, a clear mechanism of action of TQ has not been elucidated. TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India.
authors.forename: H
authors.initials: H
authors.lastname: Zubair
authors.forename: H Y
authors.initials: HY
authors.lastname: Khan
authors.forename: A
authors.initials: A
authors.lastname: Sohail
authors.forename: S
authors.initials: S
authors.lastname: Azim
authors.forename: M F
authors.initials: MF
authors.lastname: Ullah
authors.forename: A
authors.initials: A
authors.lastname: Ahmad
authors.forename: F H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: S M
authors.initials: SM
authors.lastname: Hadi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013890:Thiourea / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D002614:Chelating Agents; D016166:Free Radical Scavengers; D010618:Phenanthrolines; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D003300:Copper; C002701:neocuproine; D004247:DNA; C427203:calf thymus DNA; C002478:bathocuproine; D013890:Thiourea; C003466:thymoquinone