Vitamin D (vit D) is a known anticancer molecule, and cancer cells are reported to have elevated levels of Cu(II) ions. In this study, we show that interaction of vit D and Cu(II) leads to the formation of hydroxyl free radicals, superoxide anion and hydrogen peroxide, which causes severe oxidative stress, selectively in malignant cells. We show that the production of these reactive oxygen species causes cellular DNA fragmentation which may cause cell death. A novel putative chemical mechanism explaining how vit D causes cell death by DNA damage, selectively in malignant cells, is proposed.
Vitamin D Cu(II) Pro-oxidant Reactive oxygen species Cancer
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AR is supported by UGC-CSIR Junior Research Fellowship from the Govt. of India. The authors are grateful to Prof. M. Mushfiq and Dr. Saltanat of Dept. of Chemistry, AMU, who helped work out the reaction mechanism. AR wishes to thanks Khursid Alam Khan (Dept of Wildlife Sciences, AMU) for his support while this work was in progress.
Chibber S, Hasan I, Farhan M, Naseem I. In vitro pro-oxidant action of methotrexate in presence of white light. J Photochem Photobiol B Biol. 2011;104:387–93.CrossRefGoogle Scholar
Nasulewis A, Mazur A, Opolski A. Role of copper in angiogenesis: clinical-implication. J Trace Elem Med Biol. 2004;18:1–8.CrossRefGoogle Scholar
Kagawa TF, Geierstanger BH, Wang AHJ, Ho PS. Covalent modification of guanine bases in double stranded DNA: the 1:2-AZ-DNA structure of dc(CACACG) in the presence of CuCl2. J Biol Chem. 1991;266:20175–84.PubMedGoogle Scholar
Ebadi E, Swanson S. The status of zinc, copper and metallothionein in cancer patients. Prog Clin Biol Res. 1998;259:167–75.Google Scholar
Yoshida D, Ikada Y, Nakayama S. Quantitative analysis of copper, zinc and copper/zinc ratio in selective human brain tumors. J Neurooncol. 1993;16:109–15.CrossRefPubMedGoogle Scholar
Chibber C, Hasan I, Farhan M, Naseem I. Light mediated interaction of methotrexate with transition metal Cu (II). Med Chem Res. 2012;21:2379–87.CrossRefGoogle Scholar
Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, et al. Role of vitamin D in cancer prevention. Am J Pub Health. 2006;96:252–61.CrossRefGoogle Scholar
Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: global perspective. Ann Epidemiol. 2009;19:468–83.CrossRefPubMedGoogle Scholar
Nakayama T, Kimura T, Kodama M, Nagata C. Generation of hydrogen peroxide and superoxide anion from active metabolites of napthylamine and amino azodyes: its possible role in carcinogenesis. Carcinogenesis. 1983;4:765–9.CrossRefPubMedGoogle Scholar
Gutteridge JM. Reactivity of hydroxyl and hydroxyl-like radicals discriminated by release of thiobarbituric acid-reactive material from deoxy sugars, nucleosides and benzoate. Biogeosciences. 1984;224:761–7.Google Scholar
Ramanathan L, Das NP. Studies on the control of lipid oxidation in ground fish by some polyphenolic natural products. J Agric Food Chem. 1992;40:17–21.CrossRefGoogle Scholar
Singh NP, McCoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res. 1988;175:184–91.CrossRefPubMedGoogle Scholar
Tisato F, Marzano C, Porchia M, Pellei M, Santini C. Copper in diseases and treatments, and copper-based anticancer strategies. Med Res Rev. 2010;30:708–49.PubMedGoogle Scholar
Hadi SM, Asad SF, Singh S, Ahmad A. Putative mechanism for anticancer and apoptosis inducing properties of plant derived polyphenolic compounds. IUBMB Life. 2002;50:167–71.Google Scholar
Hadi SM, Bhat SH, Azmi A, Hanif S, Shamim U, Ullah MF. Oxidative breakage of cellular DNA by plant polyphenols: putative mechanism for their anticancer properties. Semin in Cancer Biol. 2007;17:370–6.CrossRefGoogle Scholar
Ullah MF, Khan HY, Zubair H, Shamim U, Hadi SM. The antioxidant ascorbic acid mobilizes nuclear copper leading to prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Chemoth Pharamacol. 2011;67:103–10.CrossRefGoogle Scholar
Koren R, Naor IH, Zuch E, Rotem C, Liberman UA, Ravid A. Vitamin D is a prooxidant in breast cancer. Can Res. 2001;61:1439–44.Google Scholar