Abstract
BackgroundVitamin 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.MethodsUsing 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.ResultsLipid 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.ConclusionThis 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.
Highlights
Vitamin D3 is obtained from food or is synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation
Vitamin D3 is hydroxylated at C-25 by vitamin D 25 hydroxylase or cytochrome P450 and forms 25-hydroxyvitamin D3 (25(OH)D3). 25(OH)D3 is transported to the kidney where in the proximal renal tubule it is hydroxylated at C-1 resulting in the formation of the hormonally active from of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) or calcitriol which is an essential nutrient that mediates a variety of metabolic processes [1]
Assays for lipid peroxidation, protein carbonylation and DNA damage as a consequence of calcitriol-Cu (II) interaction were performed on the isolated lymphocyte system
Summary
Vitamin D3 is obtained from food (fortified dairy products and fish oils) or is synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. 25(OH)D3 is transported to the kidney where in the proximal renal tubule it is hydroxylated at C-1 resulting in the formation of the hormonally active from of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) or calcitriol which is an essential nutrient that mediates a variety of metabolic processes [1]. The wide variety of malignant cells that respond to fluctuating levels of calcitriol indicates the widespread role of calcitriol in mediating anti-cancer effects. The precise reason for elevation in copper levels during malignancy remains unclear, increased angiogenesis is thought to be a possible reason [11]. Biochemical and structure-related data [12,13,14,15,16,17,18], we discuss the possibility that the Vitamin D Receptor (VDR) serves as an “adaptor protein” that mediates this process. To the best of our knowledge, the present research is the first report which shows that Cu (II) plays a role in calcitriol-mediated cell death
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