title: Novel Platinum(II) compounds modulate insulin-degrading enzyme activity and induce cell death in neuroblastoma cells.
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.
authors.affiliation: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy.
authors.forename: Grazia R
authors.initials: GR
authors.lastname: Tundo
authors.affiliation: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Sbardella
authors.affiliation: CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy.|Department of Environmental Biological Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: De Pascali
authors.affiliation: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ciaccio
authors.affiliation: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Coletta
authors.affiliation: CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy.|Department of Environmental Biological Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Fanizzi
authors.affiliation: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy. stefano.marini@uniroma2.it.|CIRCMSB, Via C. Ulpiani 27, 70125, Bari, Italy. stefano.marini@uniroma2.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Marini
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007339:Insulysin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007700:Kinetics; D009447:Neuroblastoma / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D007339:Insulysin