title: Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl-thiourea-Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells.
abstract: Six bipyridyl complexes of platinum(II) with thiourea, with different substituents on thiourea moiety [Pt(bipy)(R,R'NCSNR'',R''')(2)]Cl(2) (bipy=2,2'-bipyridine: R=R'=R''=R''' =H; R=Me, R'=R''=R'''=H; R=n-Bu, R'=R''=R'''=H; R=Et, R'=H, R''=Et, R'''=H; R=p-tolyl, R'=R''=R'''=H; R=phenyl, R'=H, R''=phenyl, R'''=H), rationally designed to intercalate into DNA, have been tested against a cisplatin (cDDP)-sensitive human ovarian carcinoma cell line (2008) and its -resistant variant (C13( *)). We show here that the anti-proliferative efficacy of these drugs was dependent on molecular structure, since it increased with ancillary ligand bulkiness and hydrophobicity of substituents on thiourea moiety. In particular, the presence of two phenyl groups on thiourea moiety confers an outstanding cytotoxicity. The increasing cell growth inhibition along the series of complexes partially paralleled with drug accumulation, particularly in resistant cells, but not with drug intercalation into DNA since all compounds exerted comparable ethidium bromide displacement ability. The cDDP-resistant phenotype seems, at least in part, to be involved in the action of these compounds, since the level of cross-resistance established for most complexes appeared to be in agreement with the observed impairment of drug accumulation in the resistant subline. These findings indicate that resistance to alkylating agents such as cDDP confers low level of cross-resistance to this class of DNA intercalators, which, however, depending on substituents on thiourea moiety may present remarkable cell growth inhibition even of resistant cells.
authors: Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena e Reggio Emilia, Via Campi 287, 41100 Modena, Italy. gaetano.marverti@unimore.it
authors: Gaetano
authors: G
authors: Marverti
authors: Matteo
authors: M
authors: Cusumano
authors: Alessio
authors: A
authors: Ligabue
authors: Maria Letizia
authors: ML
authors: Di Pietro
authors: Pasquale Antonio
authors: PA
authors: Vainiglia
authors: Angela
authors: A
authors: Ferrari
authors: Margherita
authors: M
authors: Bergomi
authors: Maria Stella
authors: MS
authors: Moruzzi
authors: Chiara
authors: C
authors: Frassineti
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010051:Ovarian Neoplasms / Q000473:pathology*; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013890:Thiourea / Q000737:chemistry*
chemical_list: D007364:Intercalating Agents; D017671:Platinum Compounds; D015082:2,2'-Dipyridyl; D004247:DNA; D013890:Thiourea; D002945:Cisplatin