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

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 cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

“…Complex 3 was more active than cisplatin in MIA cells, equivalent to cisplatin in A431 cells, and was comparable to 4ꞌ against HT29, MCF-7, A2780 and BE2-C lines (Figure 7). 18,20,39 and that the proposed mechanism of action of kiteplatin is the formation of DNA adducts that are harder to remove than those of cisplatin, 10 it is possible that the benefits of 1,4-dach over 1,2-dach only apply to the formation of covalent platinum-DNA adducts, which are not relevant for PPCs.…”

“…The A L is usually a 1,2diaminocyclohexane (1,2-dach) analogue, either 1S, 2S (SS-dach) or 1R, 2R (RR-dach). These PCs are active against cisplatin-resistant cell lines, 18 induce cell death in cancerous cells by a caspaseindependent mechanism, [18][19][20] and bind to DNA through non-covalent intercalation. 21 In particular, the lead complex [Pt(5,6-dimethyl-phen)(SS-dach)]Cl 2 (56MESS, Figure 1) is up to 100 times more active than cisplatin in several cell lines, with nanomolar activity against L1210 murine leukaemia and Du145 prostate cancer cells.…”

Platinum Intercalators of DNA as Anticancer Agents

“…Complementary DNA microarrays have been used to measure the genome‐wide gene expression changes of Saccharomyces cerevisiae to treatment with 56MESS ( D3 ) . From the microarray data for the 5841 genes that make up the yeast genome, 48 genes were up‐regulated and 45 genes were down‐regulated relative to the control.…”

Transition Metal Intercalators as Anticancer Agents—Recent Advances

“…To rationalise such a large difference in cytotoxicity, a comparative transcriptomics approach was undertaken between Pt2 and cisplatin to distinguish the regulation of molecular pathways using the model organism Saccharomyces cerevisiae (yeast) [28,29]. Distinct differences were observed between treatment with Pt2 and cisplatin at a molecular level, with stark contrasts in the up- and down-regulation of numerous molecular pathways.…”