A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: implications for anticancer
Oliver Rackham1, Scott J Nichols, Peter J Leedman
1Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and Center for Medical Research, The University of Western Australia, Perth, Western Australia 6000, Australia.
Abstract:
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.
Insights
A novel gold complex selectively targets breast cancer cells by inducing apoptosis through the mitochondria. This anticancer agent inhibits key enzymes, offering a promising therapeutic strategy with reduced toxicity.
Area of Science:
- Coordination Chemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Bis-chelated gold(I) phosphine complexes show anticancer potential but suffer from toxicity and lack of selectivity.
- Developing targeted cancer therapies with improved efficacy and reduced side effects is crucial.
Purpose of the Study:
- To investigate the anticancer activity and selectivity of a new water-soluble bis-chelated gold(I) complex, [Au(d2pypp)(2)]Cl, containing the novel ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp).
- To elucidate the mechanism of action and molecular basis for selectivity in breast cancer cells.
Main Methods:
- Synthesis and characterization of the gold(I) complex [Au(d2pypp)(2)]Cl.
- Evaluation of cytotoxicity and apoptosis induction in breast cancer and normal breast cell lines.
- Mitochondrial pathway analysis: assessment of mitochondrial membrane potential, glutathione levels, and caspase activation.
- Investigation of the complex's effect on thioredoxin and thioredoxin reductase activity in both cell types.
Main Results:
- The gold complex [Au(d2pypp)(2)]Cl selectively induced apoptosis in breast cancer cells at submicromolar concentrations, sparing normal cells.
- Apoptosis was mediated by the mitochondrial pathway, involving mitochondrial membrane depolarization, glutathione depletion, and caspase-3/9 activation.
- The complex accumulated in cancer cell mitochondria and exhibited greater inhibition of thioredoxin/thioredoxin reductase in cancer cells compared to normal cells.
Conclusions:
- The novel gold(I) complex [Au(d2pypp)(2)]Cl demonstrates significant selectivity and efficacy against breast cancer cells via mitochondrial-targeted apoptosis.
- Differential inhibition of the thioredoxin/thioredoxin reductase system contributes to the observed selectivity.
- This complex represents a promising candidate for developing mitochondria-targeted chemotherapeutics with enhanced safety profiles.
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