title: Mobilization of Copper ions by Flavonoids in Human Peripheral Lymphocytes Leads to Oxidative DNA Breakage: A Structure Activity Study.
abstract: Epidemiological studies have linked dietary consumption of plant polyphenols with lower incidence of various cancers. In particular, flavonoids (present in onion, tomato and other plant sources) induce apoptosis and cytotoxicity in cancer cells. These can therefore be used as lead compounds for the synthesis of novel anticancer drugs with greater bioavailability. In the present study, we examined the chemical basis of cytotoxicity of flavonoids by studying the structure-activity relationship of myricetin (MN), fisetin (FN), quercetin (QN), kaempferol (KL) and galangin (GN). Using single cell alkaline gel electrophoresis (comet assay), we established the relative efficiency of cellular DNA breakage as MN > FN > QN > KL > GN. Also, we determined that the cellular DNA breakage was the result of mobilization of chromatin-bound copper ions and the generation of reactive oxygen species. The relative DNA binding affinity order was further confirmed using molecular docking and thermodynamic studies through the interaction of flavonoids with calf thymus DNA. Our results suggest that novel anti-cancer molecules should have ortho-dihydroxy groups in B-ring and hydroxyl groups at positions 3 and 5 in the A-ring system. Additional hydroxyl groups at other positions further enhance the cellular cytotoxicity of the flavonoids.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India. arifkap@gmail.com.
authors.forename: Hussain
authors.initials: H
authors.lastname: Arif
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India. nida.rehmani4@gmail.com.
authors.forename: Nida
authors.initials: N
authors.lastname: Rehmani
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India. farhan@mohdfarhan.com.
authors.forename: Mohd
authors.initials: M
authors.lastname: Farhan
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. ahmada@karmanos.org.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India. smhadi@vsnl.com.
authors.forename: Sheikh Mumtaz
authors.initials: SM
authors.lastname: Hadi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002413:Cations, Divalent; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D020552:Comet Assay; D003300:Copper / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D053938:DNA Fragmentation / Q000187:drug effects; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D044949:Kaempferols / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002413:Cations, Divalent; D002614:Chelating Agents; D005419:Flavonoids; D044948:Flavonols; D044949:Kaempferols; D017382:Reactive Oxygen Species; C037032:galangin; C006552:kaempferol; C040015:myricetin; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; D011794:Quercetin; C017875:fisetin
keywords: Isothermal Titration Calorimetric Measurements; comet assay; flavonoids; hydroxyl group positions; molecular docking; structure activity relationship