Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and—resistant human ovarian cancer cells

Autor: Alessio Ligabue, Maria Giuseppina Monti, Federica I. Wolf, Leonarda Troiano, Stefano Iotti, Monica Montanari, Elena Di Vono, Matteo Cusumano, Gaetano Marverti, Davide Guerrieri, Maria Letizia Di Pietro, Giovanna Farruggia, Chiara Frassineti
Přispěvatelé: Marverti G, Ligabue A, Montanari M, Guerrieri D, Cusumano M, Di Pietro ML, Troiano L, Di Vono E, Iotti S, Farruggia G, Wolf F, Monti MG, Frassineti C.
Rok vydání: 2009
Předmět:
magnesium ion
Cell Membrane Permeability
Organoplatinum Compounds
Membrane permeability
Cell Survival
DNA damage
Intracellular Space
cisplatin
antineoplastic metal complex
Biology
resistance
Cell Fusion
chemistry.chemical_compound
2
2'-Dipyridyl
Settore MED/04 - PATOLOGIA GENERALE
Cell Line
Tumor
magnesio
medicine
Humans
Magnesium
Pharmacology (medical)
bipyridyl diphenyl thiourea platinum complex
Inner mitochondrial membrane
Cell Proliferation
Membrane Potential
Mitochondrial
Ovarian Neoplasms
Pharmacology
Cisplatin
chemistry.chemical_classification
Reactive oxygen species
Cisplatin-resistance
DNA intercalators
Ovarian cancer cells
Topoisomerase II
Mg2+ content
Dose-Response Relationship
Drug
Cell growth
Cell Cycle
DNA
Neoplasm
Molecular biology
Intercalating Agents
Mitochondria
Comet assay
DNA Topoisomerases
Type II
Oncology
Thiourea
chemistry
Biochemistry
Drug Resistance
Neoplasm
Female
Drug Screening Assays
Antitumor
Reactive Oxygen Species
medicine.drug
Zdroj: Investigational New Drugs. 29:73-86
ISSN: 1573-0646
0167-6997
DOI: 10.1007/s10637-009-9336-3
Popis: The cellular effects of a novel DNA-intercalating agent, the bipyridyl complex of platinum(II) with diphenyl thiourea, [Pt(bipy)(Ph(2)-tu)(2)]Cl(2), has been analyzed in the cisplatin (cDDP)-sensitive human ovarian carcinoma cell line, 2008, and its -resistant variant, C13* cells, in which the highest accumulation and cytotoxicity was found among six related bipyridyl thiourea complexes. We also show here that this complex causes reactive oxygen species to form and inhibits topoisomerase II activity to a greater extent in the sensitive than in the resistant line. The impairment of this enzyme led to DNA damage, as shown by the comet assay. As a consequence, cell cycle distribution has also been greatly perturbed in both lines. Morphological analysis revealed deep cellular derangement with the presence of cellular masses, together with increased membrane permeability and depolarization of the mitochondrial membrane. Some of these effects, sometimes differentially evident between the two cell lines, might also be related to the decrease of total cell magnesium content caused by this thiourea complex both in sensitive and resistant cells, though the basal content of this ion was higher in the cDDP-resistant line. Altogether these results suggest that this compound exerts its cytotoxicity by mechanisms partly mediated by the resistance phenotype. In particular, cDDP-sensitive cells were affected mostly by impairing topoisomerase II activity and by increasing membrane permeability and the formation of reactive oxygen species; conversely, mitochondrial impairment appeared to play the most important role in the action of complex F in resistant cells.
Databáze: OpenAIRE
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