The widespread clinical use of platinum compounds in cancer chemotherapy has prompted a search for new platinum agents. While there has been some success in lowering the toxicity of platinum drugs (carboplatin) and limited success in overcoming acquired cisplatin resistance (oxaliplatin) there has been little success in developing drugs that show activity in cancer cell lines that have a natural resistance to cisplatin and carboplatin. Recent work on the targeting of antitumor agents to DNA by the use of DNA minor groove-binding ligands has shown that this strategy can greatly enhance both the in vitro cytotoxicity and the in vivo antitumor activity of the alkylating moiety, when compared with untargeted compounds of similar reactivity. Berenil (1,3-bis(4’-amidinophenyl)triazene) can exhibit intercalative, as well as minor groove binding, properties when it binds to both DNA and RNA duplexes, while also exhibiting a preference for DNA duplexes with unobstructed minor grooves. Berenil preferentially recognizes and binds to AT-rich DNA sequences and it is strong catalytic inhibitor of mammalian DNA topoisomerase II. Based on this strategy and due to the high affinity of berenil for the minor groove, we are expecting that Pt₂(2-picoline)₄(berenil)₂ (KB1) would localize in the vicinity of the DNA, and the combined effect resulting from platination and minor groove binding might confer cytotoxic activity of Pt₂(2-picoline)₄(berenil)₂. Evaluation of the cytotoxicity of a novel dinuclear platinum(II) complex of formula Pt₂(2-picoline)₄(berenil)₂ employing a MTT assay and inhibition of [³H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that KB1 was more active than cisplatin. The DNA-binding ability of Pt₂(2-picoline)₄(berenil)₂ was evaluated by an ethidium displacement assay indicated that the complex shows strong specificity for AT base pairs in the minor groove of DNA. We have shown in the present report that Pt₂(2-picoline)₄(berenil)₂ in opposite to cisplatin is potent catalytic inhibitors of topoisomerase II. KB1 was also compared to cisplatin in respect to collagen biosynthesis, b₁-integrin receptor, IGF-I receptor, phosphorylated MAP-kinases (ERK₁/ERK₂ and p38), phosphorylated Akt kinase expression and appearance of apoptosis in MCF-7 and MDA-MB-231 human breast cancer cells. It was found that KB1 was more active inhibitor of collagen biosynthesis than cisplatin. The expression of IGF-I and β₁ integrin receptor, as well as phosphorylated MAPK, (ERK₁ and ERK₂ and p38) was significantly increased in cells incubated for 24 h with 20 mM KB1 compared to the control, not treated cells. The phenomenon was related to the increase expresion of NF-kB by KB1 as shown by Western immunoblot analysis. Flow cytometric analysis and a fluorescent microscopy assay showed that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. These results indicate Pt₂(2-picoline)₄(berenil)₂  represents multifunctional inhibitor of breast cancer cells growth and metabolism.

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