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A potent cytotoxic photoactivated platinum complex.

ABSTRACT: We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(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.

SUBMITTER: Mackay FS

PROVIDER: S-EPMC2410072 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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A potent cytotoxic photoactivated platinum complex.

Mackay Fiona S FS Woods Julie A JA Heringová Pavla P Kaspárková Jana J Pizarro Ana M AM Moggach Stephen A SA Parsons Simon S Brabec Viktor V Sadler Peter J PJ

Proceedings of the National Academy of Sciences of the United States of America 20071219 52

We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(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 ...[more]

PMID: 18093923

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Project description:UnlabelledPlatinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane)platinum(II)](2+) (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p???0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatin-resistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.Electronic supplementary materialThe online version of this article (doi:10.1007/s12154-011-0070-x) contains supplementary material, which is available to authorized users.

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A potent cytotoxic photoactivated platinum complex.

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A potent cytotoxic photoactivated platinum complex.

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