title: [RuII(η⁵-C₅H₅)(bipy)(PPh₃)]⁺, a promising large spectrum antitumor agent: cytotoxic activity and interaction with human serum albumin.
abstract: Ruthenium complexes hold great potential as alternatives to cisplatin in cancer chemotherapy. We present results on the in vitro antitumor activity of an organometallic 'Ru(II)Cp' complex, [Ru(II)Cp(bipy)(PPh(3))][CF(3)SO(3)], designated as TM34 (PPh(3) = triphenylphosphine; bipy = 2,2'-bipyridine), against a panel of human tumor cell lines with different responses to cisplatin treatment, namely ovarian (A2780/A2780cisR, cisplatin sensitive and resistant, respectively), breast (MCF7) and prostate (PC3) adenocarcinomas. TM34 is very active against all tumorigenic cell lines, its efficacy largely surpassing that of cisplatin (CisPt). The high activity of TM34 towards CisPt resistant cell lines possibly suggests a mechanism of action distinct from that of CisPt. The effect of TM34 on the activity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) involved in DNA repair mechanisms and apoptotic pathways was also evaluated, and it was found to be a strong PARP-1 ruthenium inhibitor in the low micromolar range (IC(50)=1.0 ± 0.3 μM). TM34 quickly binds to human serum albumin forming a 1:1 complex with a conditional stability constant (log K'~4.0), comparable to that of the Ru(III) complex in clinical trial KP1019. This indicates that TM34 can be efficiently transported by this protein, possibly being involved in its distribution and delivery if the complex is introduced in the blood stream. Albumin binding does not affect TM34 activity, yielding an adduct that maintains cytotoxic properties (against A2780 and A2780cisR cells). Altogether, the properties herein evaluated suggest that TM34 could be an anticancer agent of highly relevant therapeutic value.
authors.affiliation: Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande 1749-016 Lisboa, Portugal. isabel.tomaz@fc.ul.pt
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Tomaz
authors.forename: Tamás
authors.initials: T
authors.lastname: Jakusch
authors.forename: Tânia S
authors.initials: TS
authors.lastname: Morais
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques
authors.forename: Rodrigo F M
authors.initials: RF
authors.lastname: de Almeida
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.forename: Eva A
authors.initials: EA
authors.lastname: Enyedy
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: João Costa
authors.initials: JC
authors.lastname: Pessoa
authors.forename: Tamás
authors.initials: T
authors.lastname: Kiss
authors.forename: M Helena
authors.initials: MH
authors.lastname: Garcia
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D011485:Protein Binding; D012428:Ruthenium; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D009942:Organometallic Compounds; D012709:Serum Albumin; C583564:eta5-cyclopentadienyl(2,2'-bipyridyl)(triphenylphosphane)ruthenium(II); D012428:Ruthenium; D002945:Cisplatin