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Sammichele di Bari, Italy

Tundo G.R.,University of Rome Tor Vergata | Sbardella D.,University of Rome Tor Vergata | De Pascali S.A.,CIRCMSB | De Pascali S.A.,University of Salento | And 5 more authors.
Journal of Biological Inorganic Chemistry

The properties of three novel Platinum(II) compounds toward the insulin-degrading enzyme (IDE) enzymatic activity have been investigated under physiological conditions. The rationale of this study resides on previous observations that these compounds, specifically designed and synthesized by some of us, induce apoptosis in various cancer cell lines, whereas IDE has been proposed as a putative oncogene involved in neuroblastoma onset and progression. Two of these compounds, namely [PtCl(O,O'-acac)(DMSO)] and [Pt(O,O'-acac)(γ-acac)(DMS)], display a modulatory behavior, wherefore activation or inhibition of IDE activity occurs over different concentration ranges (suggesting the existence of two binding sites on the enzyme). On the other hand, [Pt(O,O'-acac)(γ-acac)(DMSO)] shows a typical competitive inhibitory pattern, characterized by a meaningful affinity constant (K i = 0.95 ± 0.21 μM). Although all three compounds induce cell death in neuroblastoma SHSY5Y cells at concentrations exceeding 2 μM, the two modulators facilitate cells' proliferation at concentrations ≤ 1.5 μM, whereas the competitive inhibitor [Pt(O,O'-acac)(γ-acac)(DMSO)] only shows a pro-apoptotic activity at all investigated concentrations. These features render the [Pt(O,O'-acac)(γ-acac)(DMSO)] a promising "lead compound" for the synthesis of IDE-specific inhibitors (not characterized yet) with therapeutic potentiality. © 2014 SBIC. Source

Tundo G.R.,University of Rome Tor Vergata | Sbardella D.,University of Rome Tor Vergata | Ciaccio C.,University of Rome Tor Vergata | De Pascali S.,CIRCMSB | And 8 more authors.
Journal of Inorganic Biochemistry

Cisplatin is a widely used chemotherapy drug which exerts cytotoxic activity by affecting both nuclear and cytosolic pathways. Herewith, we report, for the first time, that cisplatin inhibits proteasome activity in vitro. Cisplatin induces a dose dependent inhibition of the three enzymatic activities of proteasome (i.e., the chymotrypsin-like activity, the trypsin-like activity and the caspase-like activity). Moreover, cisplatin administration to neuroblastoma cells brings about a fast loss of proteasome particle activity, which is followed by a de novo synthesis of proteasome. Lastly, we report that the simultaneous administration of lactacystin and cisplatin enhances the cytotoxicity of cisplatin alone. The overall bulk of data opens to an intriguing scenario, concerning the biological effects of cisplatin in the control of cellular life, which goes beyond the well established genotoxic effect. © 2015. Source

Bisceglie F.,University of Parma | Alinovi R.,CIRCMSB | Alinovi R.,University of Parma | Pinelli S.,CIRCMSB | And 8 more authors.

In this paper we report a study conducted with two analogous complexes, bis(N4-ethylmorpholine citronellalthiosemicarbazonate) nickel(ii) and -copper(ii) on four tumour cell lines (U937, HL60, SK-N-MC and HT29). All cell lines appear to be sensitive to both metal complexes, but while in U937, HL60 and SK-N-MC, apoptosis is the main mode through which cell death occurs, HT29 cells undergo necrosis. Among the cell lines which undergo apoptosis, SK-N-MC response is characterized by the intrinsic pathway, whereas U937 and HL60 involve both the intrinsic and the extrinsic pathways. The redox activity of the two complexes provides experimental evidence that they can modulate reactive oxygen species (ROS) production as a function of both the metal and the cell line used. Among the four cell lines, HL60 does not seem to give a significant response to exposure to both compounds. In the case of the nickel derivative, ROS generation is a relatively early event, and ROS could be the mediator leading to cellular damage. HT29 shows a remarkable and rapid ROS increase and a significant induction of membrane peroxidation that could be correlated to the onset of necrosis. © 2013 The Royal Society of Chemistry. Source

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