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Int. J. Mol. Sci. 2015, 16(11), 26754-26769; doi:10.3390/ijms161125992

Mobilization of Copper ions by Flavonoids in Human Peripheral Lymphocytes Leads to Oxidative DNA Breakage: A Structure Activity Study

1
Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India
2
Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 14 September 2015 / Revised: 29 October 2015 / Accepted: 30 October 2015 / Published: 9 November 2015
(This article belongs to the Collection Advances in Molecular Oncology)
View Full-Text   |   Download PDF [7619 KB, uploaded 9 November 2015]   |  

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. View Full-Text
Keywords: flavonoids; comet assay; structure activity relationship; molecular docking; Isothermal Titration Calorimetric Measurements; hydroxyl group positions flavonoids; comet assay; structure activity relationship; molecular docking; Isothermal Titration Calorimetric Measurements; hydroxyl group positions
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Arif, H.; Rehmani, N.; Farhan, M.; Ahmad, A.; Hadi, S.M. Mobilization of Copper ions by Flavonoids in Human Peripheral Lymphocytes Leads to Oxidative DNA Breakage: A Structure Activity Study. Int. J. Mol. Sci. 2015, 16, 26754-26769.

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