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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

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Summary

The cellular effects of a novel DNA-intercalating agent, the bipyridyl complex of platinum(II) with diphenyl thiourea, [Pt(bipy)(Ph2-tu)2]Cl2, 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.

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Acknowledgements

This work was supported by a grant from MURST 60%, and from Associazione Angela Serra per la Ricerca sul Cancro, Azienda Ospedaliera Policlinico di Modena, Modena, Italy. This work has been also partially supported by PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale) 2004, MIUR, Italy.

This work was supported by an RFO grants from the University of Bologna and PRIN 2007ZT39FN from MIUR to S. Iotti.

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Authors and Affiliations

  1. Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena e Reggio Emilia, Via Campi 287, 41100, Modena, Italy

    Gaetano Marverti, Alessio Ligabue, Monica Montanari, Davide Guerrieri, Leonarda Troiano, Elena Di Vono, Maria Giuseppina Monti & Chiara Frassineti

  2. Dipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica, Università di Messina, Salita Sperone 31, 98166, Messina, Italy

    Matteo Cusumano & Maria Letizia Di Pietro

  3. Dipartimento di Medicina Interna, dell’Invecchiamento e Malattie Nefrologiche, Università di Bologna, Via Massarenti 9, 40138, Bologna, Italy

    Stefano Iotti

  4. Dipartimento di Biochimica “G. Moruzzi”, Università di Bologna, Via Irnerio 48, Bologna, Italy

    Giovanna Farruggia

  5. Istituto di Patologia Generale, Facoltà di Medicina, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Roma, Italy

    Federica Wolf

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  1. Gaetano Marverti
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Correspondence to Gaetano Marverti.

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Marverti, G., Ligabue, A., Montanari, M. et al. 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. Invest New Drugs 29, 73–86 (2011). https://doi.org/10.1007/s10637-009-9336-3

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