Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells |
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Authors: | Dr Mariafrancesca Hyeraci Dr Marialuigia Colalillo Prof Luca Labella Prof Fabio Marchetti Prof Simona Samaritani Dr Valeria Scalcon Prof Maria Pia Rigobello Prof Lisa Dalla Via |
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Affiliation: | 1. Department of Pharmaceutical and Pharmacological Sciences, Università di Padova, Via F. Marzolo, 5, 35131 Padova, Italy;2. Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy;3. Department of Biomedical Sciences, Università di Padova, Via U. Bassi 58/b, 35131 Padova, Italy |
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Abstract: | Platinum(II) complexes of the type Pt(Cl)(PPh3){(κ2-N,O)-(1{C(R)=N(OH)-2(O)C6H4})}] with R=Me, H, ( 1 and 2 ) were synthesized and characterized. Single-crystal X-ray diffraction confirmed the proposed (SP4-3) configuration for 1 . Study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the more effective. In particular, it showed a remarkable cytotoxicity in ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). Investigation into the intracellular mechanism of action demonstrated that 2 had a lower ability to platinate DNA than did cisplatin, which was taken as reference, and a notably higher uptake in resistant cells. A significant accumulation in mitochondria, along with the ability to induce concentration-dependent mitochondrial membrane depolarization and intracellular reactive oxygen species production, allowed us to propose a mitochondrion-mediated pathway as responsible for the interesting cytotoxic profile of complex 2 . |
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Keywords: | bioinorganic chemistry cytotoxicity drug resistance mitochondria platinum |
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