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, V. (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|
|Official 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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