Platinum drugs such as cisplatin, oxaliplatin and carbo-platin, are metal-based anticancer agents widely used in theclinic for the treatment of several solid tumours. The pro-totype cisplatin still represents the only antineoplastic drugwith highly curative effects in a solid malignancy such as tes-ticular cancer; oxaliplatin is used in colorectal cancer patients.Despite their efficacy, treatment with cisplatin and oxaliplatinoften results in peripheral neuropathy, representing a signifi-cant dose-limiting side effect characterized by sensory impair-ment and large myelinated sensory fiber damage due to drugaccumulation in the dorsal root ganglia (DRG). Moreover, cis-platin treatment is limited by other severe side effects suchas hepato- and nephro-toxicity and by resistance phenomena,only partially overcome by the use of oxaliplatin and car-boplatin. On the other hand, oxaliplatin is reported to beresponsible for more than 70% rate of symptomatic neuro-toxicity with any severity and often leads to treatment with-drawal. These problems have stimulated the research anddevelopment of alternative therapeutic strategies based ondifferent metals. In this work we investigated in vitro theneurotoxicity of different new water soluble anticancer com-plexes based on copper ([Cu(PTA)4]PF6and [Cu(thp)4]PF6),gold ([Au(PTA)4]PF6) and platinum ([PtCl2(cis-1,4-DACH)] and[Pt(1,1’-CBDCA)(cis-1,4-DACH)]). Neurotoxicity was evalu-ated by a well-established in vitro model based on organ-otypic cultures of DRG from 15-day-old rat embryos. Forcomparison purposes, the effect of oxaliplatin and cis-platin in terms of neurite elongation was also evaluated.At 48 hours, both copper compounds were not neuro-toxic even at higher concentrations with respect to theIC50obtained in human cancer cells while [Au(PTA)4]PF6was neurotoxic at lower concentration than IC50in cancercell lines tested. [PtCl2(cis-1,4-DACH)] elicited a neurotox-icity slightly lower with respect to oxaliplatin. Conversely,[Pt(1,1’-CBDCA)(cis-1,4-DACH)] showed a reduced neurotox-icity compared with reference platinum drugs. Since theubiquitin-proteasome system has been identified as molecu-lar target in cancer cells for the copper and gold based-drug,we evaluated by fluorimetric assay their ability to hinder theproteasome machinery in DRG neurons. Both copper-basedcompounds, that are not neurotoxic, do not inhibit protea-some activity in DRG neurons. On the contrary, the neuro-toxic complex [Au(PTA)4]PF6, induces a significant inhibitionof proteasome activity even at concentrations lower than theIC50. Our results, together with the low IC50of the copperand platinum based complexes, suggest them as promisingcompounds in anticancer treatment providing support to fur-ther studies in reliable in vivo models.

In vitro neurotoxicity of new promising metal-based anticancer complexes

PELLEI, Maura;SANTINI, Carlo;
2016-01-01

Abstract

Platinum drugs such as cisplatin, oxaliplatin and carbo-platin, are metal-based anticancer agents widely used in theclinic for the treatment of several solid tumours. The pro-totype cisplatin still represents the only antineoplastic drugwith highly curative effects in a solid malignancy such as tes-ticular cancer; oxaliplatin is used in colorectal cancer patients.Despite their efficacy, treatment with cisplatin and oxaliplatinoften results in peripheral neuropathy, representing a signifi-cant dose-limiting side effect characterized by sensory impair-ment and large myelinated sensory fiber damage due to drugaccumulation in the dorsal root ganglia (DRG). Moreover, cis-platin treatment is limited by other severe side effects suchas hepato- and nephro-toxicity and by resistance phenomena,only partially overcome by the use of oxaliplatin and car-boplatin. On the other hand, oxaliplatin is reported to beresponsible for more than 70% rate of symptomatic neuro-toxicity with any severity and often leads to treatment with-drawal. These problems have stimulated the research anddevelopment of alternative therapeutic strategies based ondifferent metals. In this work we investigated in vitro theneurotoxicity of different new water soluble anticancer com-plexes based on copper ([Cu(PTA)4]PF6and [Cu(thp)4]PF6),gold ([Au(PTA)4]PF6) and platinum ([PtCl2(cis-1,4-DACH)] and[Pt(1,1’-CBDCA)(cis-1,4-DACH)]). Neurotoxicity was evalu-ated by a well-established in vitro model based on organ-otypic cultures of DRG from 15-day-old rat embryos. Forcomparison purposes, the effect of oxaliplatin and cis-platin in terms of neurite elongation was also evaluated.At 48 hours, both copper compounds were not neuro-toxic even at higher concentrations with respect to theIC50obtained in human cancer cells while [Au(PTA)4]PF6was neurotoxic at lower concentration than IC50in cancercell lines tested. [PtCl2(cis-1,4-DACH)] elicited a neurotox-icity slightly lower with respect to oxaliplatin. Conversely,[Pt(1,1’-CBDCA)(cis-1,4-DACH)] showed a reduced neurotox-icity compared with reference platinum drugs. Since theubiquitin-proteasome system has been identified as molecu-lar target in cancer cells for the copper and gold based-drug,we evaluated by fluorimetric assay their ability to hinder theproteasome machinery in DRG neurons. Both copper-basedcompounds, that are not neurotoxic, do not inhibit protea-some activity in DRG neurons. On the contrary, the neuro-toxic complex [Au(PTA)4]PF6, induces a significant inhibitionof proteasome activity even at concentrations lower than theIC50. Our results, together with the low IC50of the copperand platinum based complexes, suggest them as promisingcompounds in anticancer treatment providing support to fur-ther studies in reliable in vivo models.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/392116
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