Novel Platinum(II) compounds modulate insulin‑degrading enzyme activity and induce cell death in neuroblastoma cells.

The properties of three novel Platinum(II) compounds toward the insulin-degrading enzyme (IDE) enzymatic activity have been investigated under physi- ological conditions. The rationale of this study resides on previous observations that these compounds, specifically designed and synthesized by some of us, induce apopto- sis in various cancer cell lines, whereas IDE has been pro- posed 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 activa- tion or inhibition of IDE activity occurs over different con- centration 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 inhibi- tory pattern, characterized by a meaningful affinity con - stant (K i = 0.95 ± 0.21 μM). Although all three com- pounds 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 inves- tigated 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.