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

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.

Calcitriol–copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma

“…Our group has previously shown that calcitriol interacts with copper and produces reactive oxygen species by Fenton-Haber-Weiss like reactions [17,18].…”

“…Our group has previously shown, cholecalciferol, the precursor of calcitriol, in the presence of free copper, produces superoxide anions and hydroxyl radicals and is capable of causing ROS mediated damage to genomic DNA [16] and that ex vivo calcitriol-copper interaction results in the generation of reactive oxygen species, which damages DNA and consequently lead to apoptosis [17]. To demonstrate that calcitriol-copper interaction is physiologically relevant, we have shown that in mice with high levels of circulating copper, calcitriol treatment causes fluctuations in free radical scavengers (possibly due to excessive formation of free radicals) and results in significant DNA damage [18].…”

Restrained management of copper level enhances the antineoplastic activity of imatinib in vitro and in vivo

“…Its vital role in catalysis of various metabolic enzymes, nerve induction, and angiogenesis along with assisting all iron mediating biological actions and boosting the immunity are well documented 10 , 11 . Intriguingly, the level of copper mounts by many folds in most of the types of cancer irrespective of the origin 12 . It is assumed that the increased copper level facilitates angiogenesis in the cancer cells 13 that is one of the reasons for chemotherapy resistance in the cells.…”

JP3 enhances the toxicity of cisplatin on drug-resistant gastric cancer cells while reducing the damage to normal cells

“…Rizvi A et al have demonstrated that calcitriol, the metabolically active form of vitamin D, interacted with copper and produced reactive oxygen species by Fenton-Haber-Weiss like reactions which caused irreparable DNA damage in carcinoma cells and induced the consequent selective cell death of malignant cells but spare normal cells. The mechanism of calcitriol-copper interaction has been confirmed in malignancy like rabbit lymphocytes 37 , human peripheral blood lymphocytes 38 and hepatocellular carcinoma rat modal 39 . It has been previously shown that cisplatin also interact with cellular copper, and this interact may in part, be responsible for its chemotherapeutic effects 40 .…”