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

摘要

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)(gamma-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)(gamma-acac)(DMSO)] shows a typical competitive inhibitory pattern, characterized by a meaningful affinity constant (K (i) = 0.95 +/- A 0.21 mu M). Although all three compounds induce cell death in neuroblastoma SHSY5Y cells at concentrations exceeding 2 mu M, the two modulators facilitate cells' proliferation at concentrations a parts per thousand currency sign 1.5 mu M, whereas the competitive inhibitor [Pt(O,O'-acac)(gamma-acac)(DMSO)] only shows a pro-apoptotic activity at all investigated concentrations. These features render the [Pt(O,O'-acac)(gamma-acac)(DMSO)] a promising "lead compound" for the synthesis of IDE-specific inhibitors (not characterized yet) with therapeutic potentiality.