title: Unravelling mechanisms behind the biological activity of bis(S-citronellalthiosemicarbazonato)nickel(II).
abstract: Bis(S-citronellalthiosemicarbazonato)nickel(II), [Ni(tcitr)2], is a compound that inhibits proliferation of tumour line U937 by inducing a G2/M block and leading the cancer cells to apoptosis. This nickel derivative shows no activity on non proliferating healthy cells. In this paper we report our studies on the action mechanisms of [Ni(tcitr)2]. Apoptosis in U937 cells exposed to [Ni(tcitr)2] takes place through activation of caspase-9, and therefore through an intrinsic triggering mechanism. Given the DNA damage observed in the Comet assay, the mutagenic activity of the metal complex was tested, including with the Ames test, micronuclei and DNA damage recovery, but neither mutagenicity nor recovery were detected. Nickel-complex-DNA interactions were analyzed by direct action of the compound on plasmidic and linear DNA by UV-vis and CD spectroscopy, gel electrophoresis and Atomic Force Microscopy. These experiments reveal that [Ni(tcitr)2] does not cause DNA breaks and does not intercalate, but significantly alters the DNA conformation creating knot-like structures and hairpins.
authors.affiliation: Dipartimento di Bioscienze, Università di Parma, Parco Area delle Scienze 11A, 43124 Parma, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Buschini
authors.forename: Silvana
authors.initials: S
authors.lastname: Pinelli
authors.forename: Rossella
authors.initials: R
authors.lastname: Alinovi
authors.forename: Francesca
authors.initials: F
authors.lastname: Mussi
authors.forename: Franco
authors.initials: F
authors.lastname: Bisceglie
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivetti
authors.forename: Nicola
authors.initials: N
authors.lastname: Doniselli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pelosi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; C555228:bis(citronellalthiosemicarbazonato)nickel(II); D004247:DNA; D053453:Caspase 9