title: In vitro and in vivo anticancer activity of copper(I) complexes with homoscorpionate tridentate tris(pyrazolyl)borate and auxiliary monodentate phosphine ligands.
abstract: Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses on the representative complexes 1 and 10, respectively. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1, and [HB(pz)3]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova , via Marzolo 5, 35131 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dolmella
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.forename: Carlo
authors.initials: C
authors.lastname: Santini
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Marina
authors.initials: M
authors.lastname: Porchia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000737:chemistry*; D001881:Borates / Q000737:chemistry*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003300:Copper; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress; D051379:Mice; D010720:Phosphines / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; D001393:Azoles; D001881:Borates; D002614:Chelating Agents; D056831:Coordination Complexes; D010720:Phosphines; D061988:Proteasome Inhibitors; D003300:Copper; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease