A potent cytotoxic photoactivated platinum complex
Mackay, Fiona S., Woods, Julie A., Heringova, Pavia, Kasparkova, Jana, Pizarro, Ana M., Moggach, Stephen A., Parsons, Simon, Brabec, Viktor and Sadler, P. J.. (2007) A potent cytotoxic photoactivated platinum complex. Proceedings of the National Academy of Sciences of the United States of America, Vol.104 (No.52). pp. 20743-20748. ISSN 0027-8424Full text not available from this repository.
Official URL: http://dx.doi.org/10.1073/pnas.0707742105
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.
|Item Type:||Journal Article|
|Divisions:||Faculty of Science > Chemistry|
|Journal or Publication Title:||Proceedings of the National Academy of Sciences of the United States of America|
|Publisher:||National Academy of Sciences|
|Date:||26 December 2007|
|Number of Pages:||6|
|Page Range:||pp. 20743-20748|
|Access rights to Published version:||Restricted or Subscription Access|
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