title: Reactivity of an antimetastatic organometallic ruthenium compound with metallothionein-2: relevance to the mechanism of action.
abstract: The reaction of metallothionein-2 (MT-2) with the organometallic antitumour compound [Ru(η(6)-p-cymene)Cl(2)(pta)], RAPTA-C, was investigated using ESI MS and ICP AES. The studies were performed in comparison to cisplatin and significant differences in the binding of the two complexes were observed. RAPTA-C forms monoadducts with MT-2, at variance with cisplatin, that has been observed to form up to four adducts. These data, combined with ICP AES analysis, show that binding of both RAPTA-C and cisplatin to MT-2 requires the displacement of an equivalent amount of zinc, suggesting that Cys residues are the target binding sites for the two metallodrugs. The competitive binding of RAPTA-C and cisplatin towards a mixture of ubiquitin (Ub) and MT-2 was also studied, showing that MT-2 can abstract RAPTA-C from Ub more efficiently than it can abstract cisplatin. The mechanistic implications of these results are discussed.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. angela.casini@epfl.ch
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Andrei
authors.initials: A
authors.lastname: Karotki
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbiani
authors.forename: Francesco
authors.initials: F
authors.lastname: Rugi
authors.forename: Milan
authors.initials: M
authors.lastname: Vašák
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000737:chemistry; D000081007:Cymenes; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D008668:Metallothionein / Q000737:chemistry* / Q000378:metabolism; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D009942:Organometallic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D011817:Rabbits; D017975:Ruthenium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D016415:Sequence Alignment; D021241:Spectrometry, Mass, Electrospray Ionization; D015032:Zinc / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D000081007:Cymenes; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); D008668:Metallothionein; D015032:Zinc; D003545:Cysteine; D002945:Cisplatin