Rational Design of Platinum(IV) Compounds to Overcome Glutathione-S-Transferase Mediated Drug Resistance

Ang, Wee Han; Khalaila, Isam; Allardyce, Claire S.; Juillerat‐Jeanneret, Lucienne; Dyson, Paul J.

doi:10.1021/ja0432618

Cited by 303 publications

(228 citation statements)

References 14 publications

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“…It may therefore be postulated that EA-CPT first binds GST P1-1 at the dimer interface, where it is subsequently reduced and cleaved, permitting the diffusion of the EA fragments to both H-sites in the enzyme. As mentioned above, release of the Pt ion has been demonstrated directly by ESI-MS on the isolated enzyme; moreover, since EA-CPT is considerably more cytotoxic than EA on a series of cell lines, [16] it is not unreasonable to infer that this process also takes place in vivo.…”

Section: Discussionmentioning

confidence: 91%

“…[16] It was also found that the GST activity of cellular extracts of treated A549 cells were low, indicating that EA-CPT was able to penetrate live mammalian cells and inhibit their GST activity. In addition, EA-CPT inhibited the cell viability of a panel of carcinoma cell lines at levels comparable to CPT.…”

Section: Abstract: Antitumor Agents · a C H T U N G T R E N N U N G Dmentioning

confidence: 99%

“…The metallocomplex comprises a trans-platinum(IV) carboxylate complex containing GST inhibitors as ligands that are released upon reduction. [16] The target molecule, ethacraplatin (EA-CPT), contains two EA moieties on the axial positions of a cis,cis,trans-diamminedichloridobiscarboxylatoplatinum(IV) framework with a CPT moiety at the equatorial site. After cell entry, the compound can be reduced intracellularly to release a cytotoxic Pt II moiety as well as two EA moieties capable of inhibiting GST enzymes.…”

Section: Abstract: Antitumor Agents · a C H T U N G T R E N N U N G Dmentioning

confidence: 99%

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Studies of Glutathione Transferase P1‐1 Bound to a Platinum(IV)‐Based Anticancer Compound Reveal the Molecular Basis of Its Activation

Parker

Italiano

Morton

et al. 2011

Chemistry A European J

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Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug-protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.

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Section: Discussionmentioning

confidence: 91%

Section: Abstract: Antitumor Agents · a C H T U N G T R E N N U N G Dmentioning

confidence: 99%

Section: Abstract: Antitumor Agents · a C H T U N G T R E N N U N G Dmentioning

confidence: 99%

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Studies of Glutathione Transferase P1‐1 Bound to a Platinum(IV)‐Based Anticancer Compound Reveal the Molecular Basis of Its Activation

Parker

Italiano

Morton

et al. 2011

Chemistry A European J

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“…Ethacraplatin (2) has the GST inhibitor ethacrynic acid, a diuretic in clinical use, attached. Reduction of ethacraplatin in the cell results in the release of two equivalents of a potent GST inhibitor together with one equivalent of the cytotoxic cisplatin [11].…”

Section: New Modes Of Interaction With the Classical Target Dnamentioning

confidence: 99%

New trends for metal complexes with anticancer activity

Bruijnincx

Sadler

2008

Current Opinion in Chemical Biology

1,214

718

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Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in 'metals in medicine'. DOI 10.1016DOI 10. /j.cbpa.2007 Introduction Medicinal inorganic chemistry [1 ,2,3] is a field of increasing prominence as metal-based compounds offer possibilities for the design of therapeutic agents not readily available to organic compounds. The wide range of coordination numbers and geometries, accessible redox states, thermodynamic and kinetic characteristics, and the intrinsic properties of the cationic metal ion and ligand itself offer the medicinal chemist a wide spectrum of reactivities that can be exploited. Although metals have long been used for medicinal purposes in a more or less empirical fashion [4], the potential of metal-based anticancer agents has only been fully realised and explored since the landmark discovery of the biological activity of cisplatin [5]. To date, this prototypical anticancer drug remains one of the most effective chemotherapeutic agents in clinical use. It is particularly active against testicular cancer and, if tumours are discovered early, an impressive cure rate of nearly 100% is achieved. The clinical use of cisplatin against this and other malignancies is, however, severely limited by dose-limiting side-effects such as neuro-, hepato-and nephrotoxicity [5]. In addition to the high systemic toxicity, inherent or acquired resistance is a second problem often associated with platinum-based drugs, which further limits their clinical use. Much effort has been devoted to the development of new platinum drugs and the elucidation of cellular responses to them to alleviate these limitations [5,6]. These problems have also prompted chemists to develop alternative strategies based on different metals and aimed at different targets. We summarize here recent activities in the field of metal-based anticancer drugs. This overview highlights some significant recent advances and illustrates emerging trends. New modes of interaction with the classical target, DNAIn classical chemotherapy, anticancer agents target DNA ...

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“…The mechanisms of action of anticancer drugs ultimately depend on their chemical structures and properties. Recently, platinum drugs with fundamentally different structures and binding modes to that of cisplatin have emerged [2,40]. Multi-nuclear platinum complexes, some of which are positively charged, capable of forming flexible and non-directional interstrand adducts with DNA have shown cytotoxic activity in tumour cells [40,52,78].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Rational Design of Platinum(IV) Compounds to Overcome Glutathione-S-Transferase Mediated Drug Resistance

Cited by 303 publications

References 14 publications

Studies of Glutathione Transferase P1‐1 Bound to a Platinum(IV)‐Based Anticancer Compound Reveal the Molecular Basis of Its Activation

Studies of Glutathione Transferase P1‐1 Bound to a Platinum(IV)‐Based Anticancer Compound Reveal the Molecular Basis of Its Activation

New trends for metal complexes with anticancer activity

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

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