title: Synthesis and in vitro anticancer activity of octahedral platinum(IV) complexes with cyclohexyl-functionalized ethylenediamine-N,N'-diacetate-type ligands.
abstract: The present study describes the synthesis and anticancer activity of novel octahedral Pt(IV) complexes with cyclohexyl functionalized ethylenediamine-N,N'-diacetate-type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s-cis is the preferred geometry of these Pt(IV) complexes with tetradentate-coordinated (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell-cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel Pt(IV) complexes against various cancer cell lines (IC(50) range: 1.9-8.7 microM) was higher than that of cisplatin (IC(50) range: 10.9-67.0 microM) and proceeded through completely different mechanisms. Cisplatin induced caspase-dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new Pt(IV) complexes caused rapid, caspase-independent, oxidative stress-mediated non-apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Jelena M
authors.initials: JM
authors.lastname: Lazić
authors.forename: Ljubica
authors.initials: L
authors.lastname: Vucićević
authors.forename: Sanja
authors.initials: S
authors.lastname: Grgurić-Sipka
authors.forename: Kristina
authors.initials: K
authors.lastname: Janjetović
authors.forename: Goran N
authors.initials: GN
authors.lastname: Kaluderović
authors.forename: Maja
authors.initials: M
authors.lastname: Misirkić
authors.forename: Maja
authors.initials: M
authors.lastname: Gruden-Pavlović
authors.forename: Dusan
authors.initials: D
authors.lastname: Popadić
authors.forename: Reinhard
authors.initials: R
authors.lastname: Paschke
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajković
authors.forename: Tibor J
authors.initials: TJ
authors.lastname: Sabo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D005029:Ethylenediamines / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D051379:Mice; D010984:Platinum / Q000737:chemistry*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005029:Ethylenediamines; D008024:Ligands; D010984:Platinum; C031234:ethylenediamine; D002945:Cisplatin