Antiproliferative activity of some novel platinum complexes on C6 glioma and MCF-7 breast cancer cells

Abstract

Cisplatin [cis-diamminedichloroplatinum(II)] was introduced into clinical practice in the early 1970s and it is one of the most active antineoplastic agents currently used in medical oncology (Barbara et al., 2006). Over the years, thousands of cisplatin analogues have been synthesized, varying the nature of the leaving groups and the carrier ligand (Matesanza and Souza, 2007; Rosenberg et al., 1969). Despite the large amount of compounds synthesized and tested, only a small number have advanced to the late stages of clinical development, that is the second-generation platinum drug carboplatin is in routine clinical use (Wang et al., 2002). Cisplatin is the best example of metal complexes and binds to DNA by coordination of the Pt atom to the N7 positions of two guanine bases or to adenine and guanine, which then block replication and/or prevent transcription. Non-covalent interactions between metal complexes and DNA include hydrogen bonding, electrostatic interaction and intercalation (Rebolledo et al., 2005; Kovala-Demertzi et al., 2003; Padhye et al., 2005). Cisplatin has a broad spectrum of activity against epithelial cancers and become the foundation of curative regimens in testicular and ovarian cancers, demonstrating significant activity also against lung, head and neck, esophagus, bladder, cervix, and endometrial cancers (Elwell et al., 2006). Although cisplatin is one of the most frequently used chemotherapeutics in the treatment of many tumors, the clinical application of cisplatin is greatly limited by its toxicity, narrow range of activity, both intrinsic and acquired resistance, and low aqueous solubility (Cui et al., 2006). In recent years, there has been an emergence of new structural types of compounds often with promising activity and able to circumvent cisplatin resistance (Van der Schilden et al., 2004; Perez et al., 2001; Kasparkova et al., 2003). The majority of platinum complexes exhibiting anti-tumor activity have two cis-leaving ligands, such as chlorides and two strongly bonded, relatively inert amine type systems (non-leaving ligands) (Ciesielska et al., 2006; Reedijk,1992). A few different liposomal formulations of cisplatin have also been prepared and biologically evaluated since the introduction of cisplatin. Nevertheless, so far none of liposomal formulations of cisplatin have been approved for the clinical use in the world. The key reasons are the poor water solubility and low lipophilicity of cisplatin, which make it difficult to efficiently encapsulate the drug in a liposome. An alternative approach is to synthesize lipophilic complexes. In addition, any work carried out in this field can be concluded that even small variations in the amine ligands of cisplatin analogues have already huge effects on the activity of the complexes. Zutphen et al. (2005) reported that new cisplatin compound composed of methylamine located cis to aminoethanol that posses promising cytotoxic activity (Abine Van Rijta et al., 2006; Van Zutphen et al., 2005). Some studies have demonstrated that Dppe as non leaving ligand has in vitro cytotoxic and in vivo antitumor activity for silver (Au-based) drugs (Berners-Price et al., 1986; Snyder et al., 1986; Mirabelli et al., 1985). Therefore, the reduction of essential cellular components or the generation of reactive radical species during phosphine oxidation, perhaps involving redoxactive metal ions such as copper and iron may play a role in the cytotoxic activity of Dppe.