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Published on: May 28, 2014
Novel Platinum(II) compounds modulate insulin-degrading enzyme activity and induce cell death in neuroblastoma cells
Grazia R Tundo1,2, Diego Sbardella1,2, Sandra A De Pascali2,3
1Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
Abstract:
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.
Insights
Three novel platinum(II) compounds were tested against insulin-degrading enzyme (IDE). One compound, [Pt(O,O'-acac)(γ-acac)(DMSO)], acts as a competitive inhibitor, showing potential for developing IDE-specific cancer therapies.
Area of Science:
- Medicinal Chemistry
- Enzymology
- Cancer Biology
Background:
- Insulin-degrading enzyme (IDE) is implicated in neuroblastoma progression.
- Novel platinum(II) compounds have demonstrated anti-cancer properties.
- Understanding IDE's role is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the effects of three novel platinum(II) compounds on insulin-degrading enzyme (IDE) activity.
- To evaluate the potential of these compounds as IDE inhibitors for cancer treatment.
- To characterize the interaction of platinum(II) compounds with IDE.
Main Methods:
- In vitro enzymatic assays were performed under physiological conditions.
- The activity of IDE was measured in the presence of varying concentrations of platinum(II) compounds.
- Cell viability and apoptosis assays were conducted using neuroblastoma cell lines.
Main Results:
- Two compounds exhibited dual modulatory behavior on IDE activity (activation/inhibition) depending on concentration.
- [Pt(O,O iterac)-acac)(γ-acac)(DMSO)] demonstrated competitive inhibition of IDE with a K i of 0.95 ± 0.21 μM.
- All compounds induced cell death in neuroblastoma cells at concentrations >2 μM, but two compounds also promoted proliferation at lower concentrations.
Conclusions:
- The competitive inhibitor [Pt(O,O iterac)-acac)(γ-acac)(DMSO)] shows significant promise as a lead compound for developing IDE-specific inhibitors.
- Targeting IDE with platinum(II) compounds could offer a novel therapeutic strategy for neuroblastoma.
- Further research is warranted to synthesize and characterize IDE-specific inhibitors based on this lead compound.
