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Open AccessArticle

The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines

1
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy
2
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 213/d, 41125 Modena, Italy
*
Authors to whom correspondence should be addressed.
Present address: Department of Biotechnology, University of Verona, 37134 Verona, Italy.
Int. J. Mol. Sci. 2019, 20(24), 6122; https://doi.org/10.3390/ijms20246122
Received: 15 November 2019 / Revised: 30 November 2019 / Accepted: 2 December 2019 / Published: 4 December 2019
(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)
Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations. The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enzymes and a marked perturbation of cell-cycle distribution in both cell lines. These findings indicate that the particular interaction of Pd(II) with phenanthroline confers the best pharmacokinetic and pharmacodynamic properties that make this class of DNA intercalators remarkable inhibitors, even of the resistant cell growth. View Full-Text
Keywords: cisplatin-resistance; DNA intercalators; ovarian cancer cells; topoisomerase II; thymidylate synthase; bipyridine; phenanthroline; Pt(II); Pd(II); thioureas cisplatin-resistance; DNA intercalators; ovarian cancer cells; topoisomerase II; thymidylate synthase; bipyridine; phenanthroline; Pt(II); Pd(II); thioureas
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Marverti, G.; Gozzi, G.; Lauriola, A.; Ponterini, G.; Belluti, S.; Imbriano, C.; Costi, M.P.; D’Arca, D. The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines. Int. J. Mol. Sci. 2019, 20, 6122.

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