期刊
METALLOMICS
卷 6, 期 8, 页码 1491-1501出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4mt00112e
关键词
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资金
- Academy of Sciences of the Czech Republic [M200041201]
- ERC [247450]
- student project of the Palacky University in Olomouc [PrF 2014 029]
- Operational Program Education for Competitiveness - European Social Fund of the Ministry of Education, Youth and Sports of the Czech Republic [CZ 1.07/2.3.00/20.0057]
- EPSRC [EP/G006792/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/G006792/1] Funding Source: researchfish
The cellular mechanism of action of an iridium(III) half-sandwich complex [(eta(5)-C5Me4C6H4C6H5)Ir(phen)Cl]PF6 (phen = phenanthroline) (1) is reported. Complex 1 was used to treat several cell lines, including cisplatin-sensitive, cisplatin-resistant (with intrinsic and acquired resistance) carcinoma cells with wild type p53 status as well as the cells with no intact p53 gene, and nontumorigenic cells. Complex 1 preferentially kills cancer cells over nontumorigenic cells and exhibits no cross-resistance with cisplatin. It appears to retain significant activity in human tumor cell lines that are refractory or poorly responsive to cisplatin, and in contrast to cisplatin it displays a high activity in human tumor cell lines that are characterized by both wild type and mutant p53 gene. The mechanism of cell killing was established through detailed cell-based assays. Complex 1 exhibits dual effects in killing cancer cells causing nuclear DNA damage and mitochondrial dysfunction involving ROS production simultaneously. Flow cytometric studies and impedance-based monitoring of cellular responses to 1 demonstrated that 1 acts more quickly than cisplatin to induce cell death and that 1 is a more effective apoptosis inducer than cisplatin in particular in early stages of treatment, when the apoptotic effects predominate over necrosis. Overall, our findings confirm that 1 and its iridium derivatives represent promising candidates for further pre-clinical studies and new additions to the growing family of nonplatinum metal-based anticancer complexes.
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