title: New platinum(IV) complex with adamantylamine ligand as a promising anti-cancer drug: comparison of in vitro cytotoxic potential towards A2780/cisR cisplatin-resistant cell line within homologous series of platinum(IV) complexes.
abstract: The aim of this study was to compare anti-tumor potency of platinum(IV) complexes with increasing hydrophobicity of their ligands. Cytotoxic potential of the new platinum(IV) complex, coded as LA-12 [(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], was compared within the series of complexes of the general formula (OC-6-43)-bis(acetato)(alkylamine)amminedichloroplatinum(IV). Alkylamine ligands with increasing hydrophobicity were: isopropylamine, cyclohexylamine, 1-adamantylamine and 3,5-dimethyl-1-adamantylamine. Particular platinum(IV) complexes were coded as LA-4, LA-2 (known as JM-216), LA-12 and LA-15, respectively. Cytotoxicity was tested with the microplate tetrazolium (MTT) assay on the panel of cancer cell lines and the results were verified by microscopy. HPLC was used to measure hydrophobicity, stability of complexes in various buffers and velocity constants for their reactivity with glutathione. Platinum(IV) complexes with bulky hydrophobic ligands (LA-12 and LA-15) demonstrated about one order higher velocity constant for pseudo-first-order reaction with glutathione in comparison to cisplatin, LA-4 and LA-2, whose velocity constants were close to those measured for cisplatin and related platinum(II) complexes. Cytotoxicities of LA-12 and LA-15 towards cisplatin-resistant epithelial carcinoma A2780/cisR were superior to cisplatin, LA-4 and LA-2 in both 24- and 72-h continuous exposure MTT tests. Rapid induction of apoptosis in the treated cancer cell lines and no cisplatin cross-resistance were found for LA-12, which is a candidate for clinical testing.
authors.affiliation: Veterinary Research Institute, Department of Immunology, Hudcova 70, 621 33 Brno, Czech Republic. turanek@vri.cz
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Turánek
authors.forename: Andrea
authors.initials: A
authors.lastname: Kasná
authors.forename: Dana
authors.initials: D
authors.lastname: Záluská
authors.forename: Jirí
authors.initials: J
authors.lastname: Neca
authors.forename: Veronika
authors.initials: V
authors.lastname: Kvardová
authors.forename: Pavlína
authors.initials: P
authors.lastname: Knötigová
authors.forename: Viktor
authors.initials: V
authors.lastname: Horváth
authors.forename: Lenka
authors.initials: L
authors.lastname: SIndlerová
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.forename: Petr
authors.initials: P
authors.lastname: Sova
authors.forename: Ales
authors.initials: A
authors.lastname: Kroutil
authors.forename: Frantisek
authors.initials: F
authors.lastname: Zák
authors.forename: Adolf
authors.initials: A
authors.lastname: Mistr
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D008024:Ligands; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D000547:Amantadine; D005978:Glutathione; D002945:Cisplatin