Water stability and cytotoxic activity relationship of a series of ferrocenium derivatives. ESR insights on the radical production during the degradation process.
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 (IC(50) 35 microM, 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.
Tabbì
Giovanni
G
Istituto di Biostrutture e Bioimmagini, CNR, Sezione di Catania, viale A. Doria 6, I-95125, Catania, Italy.
Cassino
Claudio
C
Cavigiolio
Giorgio
G
Colangelo
Donato
D
Ghiglia
Annalisa
A
Viano
Ilario
I
Osella
Domenico
D
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001761:Bleomycin / Q000494:pharmacology; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet; D019097:Spin Trapping; D014407:Tumor Cells, Cultured; D014867:Water
D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D005609:Free Radicals; C470210:decamethylferrocenium; D014867:Water; D001761:Bleomycin