DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity

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Abstract

Transition-metal-based compounds constitute a discrete class of chemotherapeutics, widely used in the clinic as antitumor and antiviral agents. Examples of established antitumor metallodrugs, routinely used in the clinic, are cisplatin [cis-diamminedichloroplatinum(II)] and its analogues carboplatin and oxaliplatin. However, drug resistance and side effects have limited their clinical utility. These limitations have prompted a search for more effective and less toxic metal-based antitumor agents. Some of the efforts have been directed in the design of non-platinum, transition-metal-based antitumor agents and ruthenium complexes have attracted much interest as alternative drugs to cisplatin in cancer chemotherapy. Ruthenium complexes demonstrate similar ligand exchange kinetics to those of platinum(II) antitumor drugs already used in the clinic while displaying only low toxicity. This is in part due to the ability of ruthenium complexes to mimic the binding of iron to molecules of biological significance, exploiting the mechanisms that the body has evolved for transport of iron. In addition, the redox potential between the different accessible oxidation states occupied by ruthenium complexes enables the body to catalyze oxidation and reduction reactions, depending on physiological environment. The biochemical changes that accompany cancer alter physiological environment, enabling ruthenium complexes to be selectively activated in cancer tissues. Due to differing ligand geometry between their complexes, ruthenium compounds bind to DNA affecting its conformation differently than cisplatin and its analogues. In addition, non-nuclear targets, such as the mitochondrion and the cell surface, have also been implicated in the antineoplastic activity of some ruthenium complexes. Thus, ruthenium compounds offer the potential over antitumor platinum(II) complexes currently used in the clinic of reduced toxicity, a novel mechanism of action, the prospect of non-cross-resistance and a different spectrum of activity. In other words, some chemical properties make ruthenium compounds well suited for medicinal applications and as an alternative to platinum antitumor drugs in the treatment of cancer cells resistant to cisplatin. Although the pharmacological target for antitumor ruthenium compounds has not been unequivocally identified, there is a large body of evidence indicating that the cytotoxicity of many ruthenium complexes correlates with their ability to bind DNA although few exceptions have been reported. This review summarizes results demonstrating that several ruthenium compounds that exhibit antitumor effects different from cisplatin or its analogues bind DNA and modify it differently than cisplatin or its analogues.

Introduction

Transition-metal-based compounds constitute a class of chemotherapeutics, which are widely used in the clinic as antitumor and antiviral agents. The interest in this structural class has its origin in the 1960s, with the serendipitous discovery by Rosenberg of the inhibition of division of bacterial cells by platinum complexes (Rosenberg et al., 1965, Rosenberg et al., 1969). The first transition-metal anticancer drug introduced in the clinic was cisplatin [cis-diamminedichloroplatinum(II)]. This very simple inorganic molecule, which belongs to bifunctional reagents, is highly effective for the treatment of testicular and ovarian cancer and is used in combination regimens for a variety of other carcinomas, including bladder, small cell lung and head and neck cancers (Weiss and Christian, 1993, Wong and Giandomenico, 1999, Giaccone, 2000, Ho et al., 2003). However, its clinical utility is limited to a relatively narrow range of tumors, because of primary resistance to cisplatin and the development of resistance secondary to the initial treatment (Wernyj and Morin, 2004). In addition, cisplatin is administered intravenously due to its limited solubility in water and has severe side effects (Wong and Giandomenico, 1999).

These limitations have prompted a search for more effective and less toxic alternative metal-based antitumor agents. The result has been the synthesis of thousands of platinum complexes and their evaluation as antitumor agents. Of these, only few have reached clinical trials and have been approved for clinical administration. They are close analogues of cisplatin, namely carboplatin [cis-diamminecyclo-butanedicarboxylato-platinum(II)], oxaliplatin {[(1R,2R-diamminocyclohexane)oxalato-platinum(II)] (1,2-diaminocyclo-hexane = DACH)} and nedaplatin [cis-diammineglycolato-platinum(II)]. Thus, the search for new metal-based antitumor drugs has continued beyond platinum, in the hope of improvements in cancer treatment.

There have been efforts to rationally design unconventional platinum complexes, such as polynuclear platinum compounds (Farrell, 2004) and analogues of clinically ineffective trans-diamminedichloroplatinum(II) (transplatin) (Farrell, 1996, Perez et al., 2000, Brabec, 2002, Natile and Coluccia, 2004, Brabec and Kasparkova, 2005a). Additional efforts have been directed in the design of other transition-metal antitumor agents (Clarke et al., 1999, Brabec, 2002, Alessio et al., 2004a). Theoretical advantages in using ions of transition metals other than platinum include:

  • a.

    the availability of additional coordination sites in octahedral complexes and altered shape of the complex,

  • b.

    alterations in ligand affinity and substitution kinetics,

  • c.

    changes in oxidation state,

  • d.

    photodynamic approaches to therapy.

Section snippets

Ruthenium complexes

Ruthenium complexes have attracted much attention as building blocks for new transition-metal-based antitumor agents. Ruthenium compounds offer the potential over antitumor platinum(II) complexes currently used in the clinic of reduced toxicity, a novel mechanism of action, the prospect of non-cross-resistance (Zeller et al., 1991, Coluccia et al., 1993) and a different spectrum of activity (Clarke, 2003, Alessio et al., 2004a). Non-cross-resistance in cisplatin-resistant cancer cells and

Conclusions and future directions

Several ruthenium compounds are transported into cells relatively easily and bind to cellular DNA. While the initial DNA binding site of several ruthenium complexes is the same as that of conventional cisplatin and its analogues, their DNA binding mode is different. The major adduct formed on DNA by cisplatin is the intrastrand cross-link formed between two neighboring purine residues. This cross-link, which is a likely candidate for the lesion responsible for antitumor effects of cisplatin,

Acknowledgements

This work was supported by grants from the Grant Agency of the CR (305/05/2030 and 203/06/1239), the Academy of Sciences of the CR (1QS500040581), and Ministry of Education of the CR (MSMT LC06030). It is a pleasure to thank all our collaborators, especially Bernhard Keppler, Enzo Alessio, and Peter J. Sadler for their expertise and for providing us with the new ruthenium complexes discussed in this review. The authors also acknowledge that this work was also carried out within the

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