Prevention of cisplatin-induced kidney epithelial cell apoptosis with a Cu superoxide dismutase-mimetic [formula omitted

Abstract

Copper 2 II ( 3 , 5 -ditertiarybutylsalicylate ) 4 ( ethanol ) 4 , Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 , was synthesized and characterized for evaluation as an anti-apoptotic superoxide dismutase (SOD)-mimetic in an in vitro 50 μM cis-diamminedichloroplatinum(II), [Pt II(NH 3) 2(Cl) 2]-treated kidney proximal tubule epithelial cell (LLC-PK) preparation. Synthesized Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 was characterized by elemental analysis, FTIR spectrophotometry, and X-ray crystallography. The IC 50 for SOD-mimetic reactivity of Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 , determined with the xanthine/xanthine oxidase/nitroblue tetrazolium (NBT) system, was found to be 2.69 μM for the binuclear chelate. Pretreatment of LLC-PK cells with 20 μM Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 prevented 50 μM Pt II(NH 3) 2(Cl) 2-induced and superoxide-mediated apoptosis. This SOD-mimetic significantly suppressed Pt II(NH 3) 2(Cl) 2-induced translocation of pro-apoptotic Bax from the cytosol to the inner mitochondrial membrane, prevented Pt II(NH 3) 2(Cl) 2-induced release of cytochrome c from the inner mitochondrial membrane and the appearance of cytochrome c in the cytosol, and prevented conversion of procaspase-3 to active caspase-3. Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 treatment inhibited Pt II(NH 3) 2(Cl) 2-mediated tubular cell injury by preventing activation of cellular mechanisms that lead to proximal tubule kidney cell death. Based on these observations, Pt II(NH 3) 2(Cl) 2- induced O 2 - -mediated apoptosis can be mechanistically overcome with a small molecular mass SOD-mimetic, Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 . Prior treatment of patients who are to undergo treatment with Pt II(NH 3) 2(Cl) 2 for their neoplastic disease with Cu 2 II ( 3 , 5 -DTBS ) 4 ( Eth ) 4 may be beneficial to these patients.