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The cytotoxicity of some ferrocenium salts and the lack of activity of the corresponding ferrocenes has been already demonstrated. The cytotoxic activity in different conditions of decamethylferrocenium tetrafluoroborate (DEMFc+) in comparison with four other ferrocenium derivatives on MCF-7 cell line is reported. The relative stability in aqueous solutions with different buffering agents is investigated by means of UV-vis spectroscopy and correlated to the cytotoxic properties of the compounds. DEMFc+, the most stable compound, shows the highest efficiency in inhibiting cell growth (IC50 35 M, for 48 h treatment). Relaxation time measurements point out the involvement of water molecules in the degradation process. ESR results confirm the ability of ferrocenium cations to produce oxygen radical species as a consequence of their degradation in water. Oxygen-dependent formation of both hydroxyl and superoxide radicals is established by the spin-trapping technique. A direct evidence of the DEMFc+ radical production into the viable cells is obtained by means of fluorescence-activated cell sorter (FACS) analysis that reveals a dose-dependent growth of 8-oxoguanine, the initial product of the guanine oxidation. This DNA oxidative stress justifies the cytotoxic effect of DEMFc+. Furthermore, the cytotoxic cooperative effect of bleomycin, an iron-dependent antitumor drug, and DEMFc+ has been tested. We have demonstrated the synergic effect between the two drugs, that is explained by the complementary oxidative damage inflicted to DNA as well as by the increasing of bleomycin activation by the iron(II/III) species available in the cell compartment from ferrocenium degradation.

Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional platinum-based drugs. In an attempt to examine the cellular basis of the preclinical antitumor efficacy of a novel multinuclear platinum compound (BBR 3464) in the treatment of cisplatin-resistant tumors, we have performed a comparative study of cisplatin and BBR 3464 in a human osteosarcoma cell line (U2-OS) and in an in vitro selected cisplatin-resistant subline (U2-OS/Pt). A marked increase of cytotoxic potency of BBR 3464 in comparison with cisplatin in U2-OS cells and a complete lack of cross-resistance in U2-OS/Pt cells were found. A detailed analysis of the cisplatin-resistant phenotype indicated that it was associated with reduced cisplatin accumulation, reduced interstrand cross-link (ICL) formation and DNA platination, microsatellite instability, and reduced expression of the DNA mismatch repair protein PMS2. Despite BBR 3464 charge and molecular size, in U2-OS and U2-OS/Pt cells, BBR 3464 accumulation and DNA-bound platinum were much higher than those observed for cisplatin. In contrast, the frequency of ICLs after exposure to BBR 3464 was very low. The time course of ICL formation after drug removal revealed a low persistence of these types of DNA lesions induced by BBR 3464, in contrast to an increase of DNA lesions induced by cisplatin, suggesting that components of the DNA repair pathway handle the two types of DNA lesions differently. The cellular response of HCT116 mismatch repair-deficient cells was consistent with a lack of influence of mismatch repair status on BBR 3464 cytotoxicity. Because BBR 3464 produces high levels of lesions different from ICLs, likely including intra-strand cross-links and monoadducts, the ability of the triplatinum complex to overcome cisplatin resistance appears to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared with conventional mononuclear complexes rather than the ability to overcome specific cellular alterations.