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Cytotoxicity and cellular response mechanisms of water-soluble platinum(II) complexes of lidocaine and phenylcyanamide derivatives

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Abstract

Three new platinum(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pt(3,5-(NO2)2pcyd)2(LC)], 1, K[Pt(3,5-(CF3)2pcyd)2(LC)], 2, K[Pt(3,5-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 3,5-(NO2)2pcyd: 3,5-dinitro phenylcyanamide, 3,5-(CF3)2pcyd: 3,5-bis(trifluoromethyl) phenylcyanamide, 3,5-Cl2pcyd: 3,5-dichloro phenylcyanamide) have been synthesized and fully characterized. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. The complexes 1–3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines. All the complexes are more active than cisplatin and follow the trend 1 > 2 > 3. Mechanistic studies showed that the trend in cytotoxicity of the Pt(II) complexes is mainly consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which consequently results in the loss of mitochondrial membrane potential and apoptosis induction. The complex 1 caused to approximately 80-fold higher DNA platination level with respect to cisplatin. The complexes 1–3 can considerably stimulate the production of hydrogen peroxide in a time-dependent manner. Also, the complexes 1–3 induced an increase in reactive oxygen species (ROS) production that was superior to that induced by antimycin. The complex 1 had the most effect on ROS production in comparison with other complexes.

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Acknowledgement

We acknowledge general support from the Department of Chemistry, Isfahan University of Technology (IUT).

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Authors and Affiliations

  1. School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland

    Leila Tabrizi

  2. Department of Chemistry, Isfahan University of Technology, Isfahan, 84156-83111, Iran

    Leila Tabrizi & Hossein Chiniforoshan

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  1. Leila Tabrizi
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  2. Hossein Chiniforoshan
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Correspondence to Leila Tabrizi or Hossein Chiniforoshan.

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Tabrizi, L., Chiniforoshan, H. Cytotoxicity and cellular response mechanisms of water-soluble platinum(II) complexes of lidocaine and phenylcyanamide derivatives. Biometals 30, 59–70 (2017). https://doi.org/10.1007/s10534-016-9986-5

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