Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator
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ORIGINAL ARTICLE
Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator Shaoyu Wang & Vincent J. Higgins & Janice R. Aldrich-Wright & Ming J. Wu
Received: 12 October 2011 / Accepted: 22 November 2011 / Published online: 6 December 2011 # Springer-Verlag 2011
Abstract Platinum-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, [(5,6dimethyl-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 cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.
Electronic supplementary material The online version of this article (doi:10.1007/s12154-011-0070-x) contains supplementary material, which is available to authorized users.
Keywords 56MESS . Platinum . Metallointercalators . Gene . Iron . Anticancer
S. Wang : V. J. Higgins : J. R. Aldrich-Wright (*) : M. J. Wu (*) School of Biomedical and Health Science, University of Western Sydney, Locked Bag 1797, Sydney, Penrith NSW 2751, Australia e-mail: [email protected] e-mail: [email protected] S. Wang School of Medicine, University of Western Sydney, Locked Bag 1797, Sydney, Penrith NSW 2751, Australia V. J. Higgins Ramaciotti Centre for Gene Function Analysis, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Paddington NSW 2052, Australia
Introduction Platinum-based anticancer drugs, cisplatin, carboplatin and oxaliplatin, have been used world-wide to t
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