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Rackham O, Nichols SJ, Leedman PJ, Berners-Price SJ, Filipovska A: A gold (I) phosphine complex selectively induces apoptosis in breast cancer cells: implications for anticancer therapeutics targeted to mitochondria. Biochem Pharmacol. 2007 Oct 1;74(7):992-1002. Epub 2007 Jul 21.
Bis-chelated gold (I) phosphine complexes have shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity and lack of selectivity for cancer cells. Here, we have investigated the anticancer activity of a new bis-chelated Au (I) bidentate phosphine complex of the novel water soluble ligand 1,3-bis (di-2-pyridylphosphino) propane (d2pypp). We show that this gold complex [Au (d2pypp)(2)] Cl, at submicromolar concentrations, selectively induces apoptosis in breast cancer cells but not in normal breast cells. Apoptosis was induced via the mitochondrial pathway, which involved mitochondrial membrane potential depolarisation, depletion of the glutathione pool and caspase-3 and caspase-9 activation. The gold lipophilic complex was accumulated in mitochondria of cells, driven by the high mitochondrial membrane potential. To address the molecular basis of the observed selectivity between the two cell lines we investigated the effect of the gold complex on the thioredoxin/thioredoxin reductase system in normal and cancer breast cells. We show that [Au (d2pypp)(2)] Cl inhibits the activities of both thioredoxin and thioredoxin reductase and that this effect is more pronounced in the breast cancer cells. This difference may account for the selective cell death seen in the breast cancer cells but not in the normal cells. Our investigation has led to new insights into the mechanism of action of bis-chelated gold (I) diphosphine complexes and their future development as mitochondria targeted chemotherapeutics. |
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