Cisplatin is the archetypal inorganic drug and it is nowadays one of the most efficient metal-based anticancer agents, targeting a large number of solid tumours. Although highly effective in treating a variety of cancers, cisplatin treatment is still limited by severe side effects such as neuro-, hepato- and nephro-toxicity and by inherited or acquired resistance phenomena, only partially overcome by the use of new platinum drugs (i.e. oxaliplatin and carboplatin). These problems have stimulated the research and development of alternative therapeutic strategies based on different heavy metals. In this work we investigated the neurotoxicity effect of two new promising water soluble anticancer complexes based on copper [Cu(PTA)4PF6] and gold [Au(PTA)4PF6]. Cisplatin and oxaliplatin neurotoxicity was also measured as reference drugs. Neurotoxicity was evaluated by an in vitro model based on the ability of NGF exposed embryonic rat dorsal root ganglia (DRG) organotypic culture to grow neurite. In particular the interference of the under study neurotoxic compound with neurite elongation was analysed. DRGs explanted from E15 rat embryos were treated for 48h with different drug concentrations including the IC50 evaluated for different tumour cell lines. In our model cisplatin and oxaliplatin resulted neurotoxic (inducing a reduction of neurite outgrowth more than 50%) at concentrations achievable in plasma of patients treated with the same drugs confirming data obtained in clinical studies. On the contrary, the neurotoxicity assay demonstrated that copper-based compound was neurotoxic at higher concentrations with respect to the IC50 obtained for all tumour cell lines tested. On the other hand preliminary neurotoxicity data suggest that gold-based compound is neurotoxic at lower concentration than IC50 calculated for almost tested cancer cell lines. Our results, together with the low IC50 of the copper compound compared to the one observed for cisplatin and oxaliplatin, suggest that copper-based drugs represent new and promising compounds in anticancer treatment.
Nicolini, G., Ceresa, C., Gandin, V., Porchia, M., Pellei, M., Santini, C., et al. (2012). In vitro properties of two water soluble heavy metal-based complexes. Intervento presentato a: 11th International Symposium on Platinum Coordination Compounds in Cancer Chemotherapy, Verona.
In vitro properties of two water soluble heavy metal-based complexes
NICOLINI, GABRIELLAPrimo
;CERESA, CECILIASecondo
;CAVALETTI, GUIDO ANGELOUltimo
2012
Abstract
Cisplatin is the archetypal inorganic drug and it is nowadays one of the most efficient metal-based anticancer agents, targeting a large number of solid tumours. Although highly effective in treating a variety of cancers, cisplatin treatment is still limited by severe side effects such as neuro-, hepato- and nephro-toxicity and by inherited or acquired resistance phenomena, only partially overcome by the use of new platinum drugs (i.e. oxaliplatin and carboplatin). These problems have stimulated the research and development of alternative therapeutic strategies based on different heavy metals. In this work we investigated the neurotoxicity effect of two new promising water soluble anticancer complexes based on copper [Cu(PTA)4PF6] and gold [Au(PTA)4PF6]. Cisplatin and oxaliplatin neurotoxicity was also measured as reference drugs. Neurotoxicity was evaluated by an in vitro model based on the ability of NGF exposed embryonic rat dorsal root ganglia (DRG) organotypic culture to grow neurite. In particular the interference of the under study neurotoxic compound with neurite elongation was analysed. DRGs explanted from E15 rat embryos were treated for 48h with different drug concentrations including the IC50 evaluated for different tumour cell lines. In our model cisplatin and oxaliplatin resulted neurotoxic (inducing a reduction of neurite outgrowth more than 50%) at concentrations achievable in plasma of patients treated with the same drugs confirming data obtained in clinical studies. On the contrary, the neurotoxicity assay demonstrated that copper-based compound was neurotoxic at higher concentrations with respect to the IC50 obtained for all tumour cell lines tested. On the other hand preliminary neurotoxicity data suggest that gold-based compound is neurotoxic at lower concentration than IC50 calculated for almost tested cancer cell lines. Our results, together with the low IC50 of the copper compound compared to the one observed for cisplatin and oxaliplatin, suggest that copper-based drugs represent new and promising compounds in anticancer treatment.
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