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.
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.
Turánek
Jaroslav
J
Veterinary Research Institute, Department of Immunology, Hudcova 70, 621 33 Brno, Czech Republic. turanek@vri.cz
Kasná
Andrea
A
Záluská
Dana
D
Neca
Jirí
J
Kvardová
Veronika
V
Knötigová
Pavlína
P
Horváth
Viktor
V
SIndlerová
Lenka
L
Kozubík
Alois
A
Sova
Petr
P
Kroutil
Ales
A
Zák
Frantisek
F
Mistr
Adolf
A
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
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D000547:Amantadine; D005978:Glutathione; D002945:Cisplatin