A potent cytotoxic photoactivated platinum complex

Fiona S. Mackay, Julie A. Woods, Pavia Heringova, Jana Kasparkova, Ana M. Pizarro, Stephen A. Moggach, Simon Parsons, Viktor Brabec, Peter J. Sadler

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Abstract

We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N-3)(2)(OH)(2)(NH3)(py)] (1) contains an octahedral Pt-IV center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the Pt-II anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine Pt-II adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido Pt-IV complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.

Original languageEnglish
Pages (from-to)20743-20748
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number52
DOIs
Publication statusPublished - 26 Dec 2007
Externally publishedYes

Cite this

Mackay, F. S., Woods, J. A., Heringova, P., Kasparkova, J., Pizarro, A. M., Moggach, S. A., Parsons, S., Brabec, V., & Sadler, P. J. (2007). A potent cytotoxic photoactivated platinum complex. Proceedings of the National Academy of Sciences of the United States of America, 104(52), 20743-20748. https://doi.org/10.1073/pnas.0707742105