Journal of Chemical Biology

, Volume 5, Issue 2, pp 51–61

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Original Article

DOI: 10.1007/s12154-011-0070-x

Cite this article as:
Wang, S., Higgins, V.J., Aldrich-Wright, J.R. et al. J Chem Biol (2012) 5: 51. doi:10.1007/s12154-011-0070-x

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, [(5,6-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.

Keywords

56MESSPlatinumMetallointercalatorsGeneIronAnticancer

Supplementary material

12154_2011_70_MOESM1_ESM.pdf (30 kb)
ESM 1(PDF 30 kb)
12154_2011_70_MOESM2_ESM.pdf (127 kb)
ESM 2(PDF 126 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.School of Biomedical and Health ScienceUniversity of Western SydneySydneyAustralia
  2. 2.School of MedicineUniversity of Western SydneySydneyAustralia
  3. 3.Ramaciotti Centre for Gene Function Analysis, School of Biotechnology and Biomolecular SciencesUniversity of New South WalesPaddingtonAustralia