title: Prevention of cisplatin-induced kidney epithelial cell apoptosis with a Cu superoxide dismutase-mimetic [copper2II(3,5-ditertiarybutylsalicylate)4(ethanol)4].
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 microM 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 microM for the binuclear chelate. Pretreatment of LLC-PK cells with 20 microM Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) prevented 50 microM 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.
authors.affiliation: Departments of Chemistry and Physics, University of Arkansas at Pine Bluff, 1200 North University Drive, Pine Bluff, AR 71601, USA. wangila_g@uapb.edu
authors.forename: Grant W
authors.initials: GW
authors.lastname: Wangila
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Nagothu
authors.forename: Richard
authors.initials: R
authors.lastname: Steward
authors.forename: Renu
authors.initials: R
authors.lastname: Bhatt
authors.forename: Peter Abeta
authors.initials: PA
authors.lastname: Iyere
authors.forename: William M
authors.initials: WM
authors.lastname: Willingham
authors.forename: John R J
authors.initials: JR
authors.lastname: Sorenson
authors.forename: Sudhir V
authors.initials: SV
authors.lastname: Shah
authors.forename: Didier
authors.initials: D
authors.lastname: Portilla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018360:Crystallography, X-Ray; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D005456:Fluorescent Dyes; D007211:Indoles; D007668:Kidney / Q000166:cytology* / Q000187:drug effects; D018374:LLC-PK1 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013482:Superoxide Dismutase / Q000378:metabolism*; D013552:Swine; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C515535:(copper2II(3,5-ditertiarybutylsalicylate)4(ethanol)4); D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D007211:Indoles; D009942:Organometallic Compounds; D051028:bcl-2-Associated X Protein; C007293:DAPI; D045304:Cytochromes c; D013482:Superoxide Dismutase; D053148:Caspase 3; D002945:Cisplatin