title: In vitro and in vivo antitumor activities and DNA binding mode of five coordinated cyclometalated organoplatinum(II) complexes containing biphosphine ligands.
abstract: New complexes [Pt(C(∧)N)Cl(dppa)] (1), and [Pt(C(∧)N)Cl(dppm)] (2), (C(∧)N. deprotonated 2-phenylpyridine; dppa. bis(diphenylphosphino)amine; dppm. bis(diphenylphosphino)methane) were suggested to have pentacoordinated geometry as investigated by NMR and conductometry. Pharmacological effects of 1 and 2 were evaluated for their proteasome-inhibitory and apoptosis-inducing activities under in vitro and in vivo conditions, showing significant proteasome-inhibitory activity against purified 20S proteasome, while 2 demonstrated superior inhibitory activity against cellular 26S proteasome. Consistently, this effect was associated with higher levels of proteasome target proteins and apoptosis induction in breast cancer cells. Importantly, preliminary studies show 1 and 2 were able to exert a similar effect in vivo by inhibiting the growth of breast cancer xenografts in mice, which was associated with proteasome inhibition and apoptosis induction. Interaction of 1 and 2 with herring sperm DNA was investigated by fluorimeteric emission, suggesting that Pt(II)-containing biphosphine complexes with DNA binding capabilities can also target and inhibit the tumor proteasome.
authors.affiliation: The Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Frezza
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Samouei
authors.forename: Mehdi
authors.initials: M
authors.lastname: Rashidi
authors.forename: Fayezeh
authors.initials: F
authors.lastname: Samari
authors.forename: Bahram
authors.initials: B
authors.lastname: Hemmateenejad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010720:Phosphines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D009944:Organoplatinum Compounds; D010720:Phosphines; D061988:Proteasome Inhibitors; D011725:Pyridines; D004247:DNA