title: In vitro antitumor activity of the water soluble copper(I) complexes bearing the tris(hydroxymethyl)phosphine ligand.
abstract: Monocationic hydrophilic complexes [Cu(thp)4](+) 3 and [Cu(bhpe)2](+) 4 were synthesized by ligand exchange reactions starting from the labile [Cu(CH3CN)4][PF6] precursor in the presence of an excess of the relevant hydrophilic phosphine. Complexes 3 and 4 were tested against a panel of several human tumor cell lines. Complex 3 has been shown to be about 1 order of magnitude more cytotoxic than cisplatin. Chemosensitivity tests performed on cisplatin and multidrug resistance phenotypes suggested that complex 3 acts via a different mechanism of action than the reference drug. Different short-term proliferation assays suggested that lysosomal damage is an early cellular event associated with complex 3 cytotoxicity, probably mediated by an increased production of reactive oxygen species. Cytological stains and flow cytometric analyses indicated that the phosphine copper(I) complex is able to inhibit the growth of tumor cells via G2/M cell cycle arrest and paraptosis accompanied with the loss of mitochondrial transmembrane potential.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, 35131 Padova, Italy. cristina.marzano@unipd.it
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.forename: Davide
authors.initials: D
authors.lastname: Colavito
authors.forename: Grazia
authors.initials: G
authors.lastname: Papini
authors.forename: Giancarlo Gioia
authors.initials: GG
authors.lastname: Lobbia
authors.forename: Elda
authors.initials: E
authors.lastname: Del Giudice
authors.forename: Marina
authors.initials: M
authors.lastname: Porchia
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Carlo
authors.initials: C
authors.lastname: Santini
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D003300:Copper; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010720:Phosphines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D008024:Ligands; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010720:Phosphines; C528851:bis(bis(bis(hydroxymethyl)phosphino)ethane)copper(I); C528850:tetrakis(tris(hydroxymethyl)phosphine)copper(I); D014867:Water; D003300:Copper; C505069:tris(hydroxymethyl)phosphine