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Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses. [ABSTRACT FROM AUTHOR]

The current study aims at preparing biocompatible hybrid organic-inorganic ruthenium core-shell nanostructures (RuNPs) coated with polyvinylpyrrolidone (PVP) and polyoxyethylene stearate (POES). Thereafter, the core/shell RuNPs are loaded with doxorubicin (to form RuPDox) with a loading efficiency > 60%. RuPDox possesses exceptional stability and pH-responsive release kinetics with approx. 50% release of doxorubicin at up to 1 h exposure to an acidic endosomal environment. The cytotoxic effects of RuPDox are tested in vitro against breast cancer (MDA-MB-231), ovarian cancer (A2780), and neuroblastoma (UKF-NB-4) cells. Notably, although RuNPs have slight cytotoxicity only, RuPDox causes a synergistic enhancement of cytotoxicity when compared to free doxorubicin. Significant increase in free radicals formation, enhanced activity of executioner caspases 3/7, and higher expression of p53 and metallothionein is further identified due to the RuPDox treatment. Single-cell gel electrophoresis reveals no additional contribution of RuNPs to genotoxicity of doxorubicin. Moreover, RuPDox promotes significantly increased stability of doxorubicin in human plasma and pronounced hemocompatibility assayed on human red blood cells. The results imply a high potential of biocompatible hybrid RuNPs with PVP-POES shell as versatile nanoplatforms to enhance the efficiency of cancer treatment. [ABSTRACT FROM AUTHOR]