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In vitro and in vivo anti-tumor effects of selected platinum(IV) and dinuclear platinum(II) complexes against lung cancer cells

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Abstract

In the present study, cytotoxic effects of cisplatin, the most usually used chemotherapeutic agent, were compared with new designed platinum(IV) ([PtCl4(en)] (en = ethylenediamine) and [PtCl4(dach)]) (dach = (±)-trans-1,2-diaminocyclohexane) and platinum(II) complexes ([{trans-Pt(NH3)2Cl}2(μ-pyrazine)](ClO4)2 (Pt1), [{trans-Pt(NH3)2Cl}2(μ-4,4′-bipyridyl)](ClO4)2DMF(Pt2),[{trans-Pt(NH3)2Cl}2(μ-1,2-bis(4pyridyl)ethane)](ClO4)2 (Pt3)), in vitro and in vivo against human and murine lung cancer cells, to determine anti-tumor potential of newly synthesized platinum-based drugs in the therapy of lung cancer. Results obtained by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], Lactate dehydrogenase and Annexin V/Propidium Iodide assays showed that, among all tested complexes, [PtCl4(en)] had the highest cytotoxicity against human and murine lung carcinoma cells in vitro. [PtCl4(en)] showed significantly higher cytotoxicity then cisplatin in all tested concentrations, mainly by inducing apoptosis in lung cancer cells. [PtCl4(en)] was well tolerated in vivo. Clinical signs of [PtCl4(en)]-induced toxicity, such as changes in food, water consumption or body weight, nephrotoxicity or hepatotoxicity was not observed in [PtCl4(en)]-treated mice. [PtCl4(en)] managed to increase presence of CD45+ leukocytes, including F4/80+ macrophages, CD11c+ dendritic cells, CD4+ helper and CD8+ cytotoxic T cells (CTLs) in the lungs, cytotoxic NK, NKT and CTLs in the spleens of tumor bearing mice, resulting with reduction of metastatic lesions in the lungs, indicating its potential to stimulate anti-tumor immune response in vivo. Due to its anti-tumor cytotoxicity, biocompatibility, and potential for stimulation of anti-tumor immune response, [PtCl4(en)] may be a good candidate for further testing in the field of medicinal chemistry.

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Acknowledgements

This work was supported by grants from the Ministry of Education, Science and Technological Development, Republic of Serbia (Projects ON175069, ON175103 and 172011).

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Authors and Affiliations

  1. Department of Thoracic Surgery, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Milos Arsenijevic

  2. Department of Microbiology and Immunology, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia

    Marija Milovanovic, Bojana Simovic Markovic & Vladislav Volarevic

  3. Department of Chemistry, Faculty of Science, University of Kragujevac, Kragujevac, Serbia

    Snezana Jovanovic

  4. Department for Preventive and Pediatric Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Natalija Arsenijevic

  5. Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Marina Gazdic

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  1. Milos Arsenijevic
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  7. Vladislav Volarevic
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Correspondence to Milos Arsenijevic.

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Arsenijevic, M., Milovanovic, M., Jovanovic, S. et al. In vitro and in vivo anti-tumor effects of selected platinum(IV) and dinuclear platinum(II) complexes against lung cancer cells. J Biol Inorg Chem 22, 807–817 (2017). https://doi.org/10.1007/s00775-017-1459-y

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  • DOI: https://doi.org/10.1007/s00775-017-1459-y

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