title: Mechanism of cytotoxicity of copper(I) complexes of 1,2-bis(diphenylphosphino)ethane.
abstract: The cytotoxic properties of arylphosphines are regulated by metals. We have synthesized a series of copper(I) complexes of 1,2-bis(diphenylphosphino)ethane (DPPE) and tested their in vitro cytotoxicity in a human lung carcinoma cell line H460. One of the complexes [Cu(2)(DPPE)(3)(CH(3)CN)(2)](ClO(4))(2) (C1), showed maximum cytotoxicity comparable to that of adriamycin. Treatment of cells with C1 caused DNA damage in vitro and activated the p53 pathway. Flow cytometry revealed that growth inhibition by C1 was due to a combination of cell cycle arrest and apoptosis. Simultaneous addition of C1 and adriamycin increased the cytotoxicity of either compound, suggesting the potential use of adriamycin in combination with C1. DNA binding and simulation studies suggest that adriamycin binds to DNA synergistically in the presence of C1. Thus, we have identified C1, a copper(I) complex of DPPE, as a potential chemotherapeutic drug for further testing, which could be used either alone or in combination with other chemotherapeutic drugs.
authors.affiliation: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Nusrat J
authors.initials: NJ
authors.lastname: Sanghamitra
authors.forename: Pornima
authors.initials: P
authors.lastname: Phatak
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Das
authors.forename: Ashoka G
authors.initials: AG
authors.lastname: Samuelson
authors.forename: Kumaravel
authors.initials: K
authors.lastname: Somasundaram
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003300:Copper; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008958:Models, Molecular; 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*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000819:agonists
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010720:Phosphines; D016159:Tumor Suppressor Protein p53; C498564:bis(acetonitrile)tris((1,2-diphenylphosphino)ethane)dicopper(I); D003300:Copper; D004317:Doxorubicin; D004247:DNA