Selective cytotoxic action and DNA damage by calcitriol-Cu(II) interaction: putative mechanism of cancer prevention.

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TitleSelective cytotoxic action and DNA damage by calcitriol-Cu(II) interaction: putative mechanism of cancer prevention.
Publication TypeJournal Article
Year of Publication2013
AuthorsRizvi, A, S Hasan, S, Naseem, I
JournalPLoS One
Volume8
Issue9
Paginatione76191
Date Published2013
ISSN1932-6203
KeywordsAnalysis of Variance, Animals, Apoptosis, Calcitriol, Chelating Agents, Comet Assay, Copper, DNA Fragmentation, Free Radicals, Lipid Peroxidation, Lymphocytes, Neoplasms, Oxidative Stress, Protein Carbonylation, Rabbits
Abstract

BACKGROUND: Vitamin D is known to play an important role in cancer-prevention. One of the features associated with the onset of malignancy is the elevation of Cu (II) levels. The mode of cancer-prevention mediated by calcitriol, the biologically active form of vitamin D, remain largely unknown.

METHODS: Using exogenously added Cu (II) to stimulate a malignancy like condition in a novel cellular system of rabbit calcitriol overloaded lymphocytes, we assessed lipid peroxidation, protein carbonylation, DNA damage and consequent apoptosis. Free radical mediators were identified using free radical scavengers and the role of Cu (II) in the reaction was elucidated using chelators of redox active cellular metal ions.

RESULTS: Lipid peroxidation and protein carbonylation (markers of oxidative stress), consequent DNA fragmentation and apoptosis were observed due to calcitriol-Cu (II) interaction. Hydroxyl radicals, hydrogen peroxide and superoxide anions mediate oxidative stress produced during this interaction. Amongst cellular redox active metals, copper was found to be responsible for this reaction.

CONCLUSION: This is the first report implicating Cu (II) and calcitriol interaction as the cause of selective cytotoxic action of calcitriol against malignant cells. We show that this interaction leads to the production of oxidative stress due to free radical production and consequent DNA fragmentation, which leads to apoptosis. A putative mechanism is presented to explain this biological effect.

DOI10.1371/journal.pone.0076191
Alternate JournalPLoS ONE
PubMed ID24086705
PubMed Central IDPMC3785422