Journal Article

Selective Cytotoxic Action and DNA Damage by Calcitriol-Cu(II) Interaction: Putative Mechanism of Cancer Prevention

Naseem, Imrana, Hasan, S. Saif, Rizvi, Asim

2013

Overview

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. 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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis of Variance / Animals / Anions / Apoptosis / Apoptosis - drug effects / Biochemistry / Biological activity / Biological effects / Breast cancer / Calcitriol / Calcitriol - metabolism / Calcitriol - toxicity / Cancer / Carbonyls / Chelating agents / Chelating Agents - metabolism / Comet Assay / Copper / Copper - metabolism / Copper - toxicity / Cytotoxicity / Damage assessment / Damage detection / Damage prevention / Deoxyribonucleic acid / DNA / DNA damage / DNA fragmentation / DNA Fragmentation - drug effects / Experiments / Fragmentation / Free radicals / Free Radicals - metabolism / Heavy metals / Hydrogen / Hydrogen peroxide / Hydroxyl radicals / Hypotheses / Life sciences / Lipid peroxidation / Lipid Peroxidation - drug effects / Lymphocytes / Malignancy / Neoplasms - prevention & control / Oxidative stress / Oxidative Stress - drug effects / Peroxidation / Prevention / Protein Carbonylation - drug effects / Rabbits / Studies / Superoxide / Superoxide anions / Vitamin D