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Platinum(IV)-nitroxyl complexes as possible candidates to circumvent cisplatin resistance in RT112 bladder cancer cells

  • Molecular Toxicology
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Abstract

The therapeutic efficacy of the anticancer drug cisplatin is limited by the development of resistance. We therefore investigated newly synthesized platinum-nitroxyl complexes (PNCs) for their potential to circumvent cisplatin resistance. The complexes used were PNCs with bivalent cis-PtII(R·NH2)(NH3)Cl2 and cis-PtII(DAPO)Ox and four-valent platinum cis,trans,cis-PtIV(R·NH2)(NH3)(OR)2Cl2 and cis,trans,cis-PtIV(DAPO)(OR)2Ox, where R· are TEMPO or proxyl nitroxyl radicals, DAPO is trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl, and OR and Ox are carboxylato and oxalato ligands, respectively. The complexes were characterized by spectroscopic methods, HPLC, log P ow data and elemental analysis. We studied intracellular platinum accumulation, DNA platination and cytotoxicity upon treatment with the PNCs in a model system of the bladder cancer cell line RT112 and its cisplatin-resistant subline RT112-CP. Platinum accumulation and DNA platination were similar in RT112 and RT112-CP cells for both bivalent and four-valent PNCs, in contrast to cisplatin for which a reduction in intracellular accumulation and DNA platination was observed in the resistant subline. The PNCs were found to platinate DNA in relation to the length of their axial RO-ligands. Furthermore, the PNCs were increasingly toxic in relation to the elongation of their axial RO-ligands, with similar toxicities in RT112 and its cisplatin-resistant subline. Using a cell-free assay, we observed induction of oxidative DNA damage by cisplatin but not PNCs suggesting that cisplatin exerts its toxic action by platination and oxidative DNA damage, while cells treated with PNCs are protected against oxidatively induced lesions. Altogether, our study suggests that PNCs may provide a more effective treatment for tumors which have developed resistance toward cisplatin.

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Acknowledgments

High-resolution ESMS spectra were recorded in the Department of Structural Studies of Zelinsky Institute of Organic Chemistry, Moscow. The work was supported by Deutsche Forschungsgemeinschaft (DFG), Exzellenzinitiative KIT and Russian Scientific Fund (RSF) Grant No. 14-23-00018.

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    Authors and Affiliations

    1. Food Chemistry and Toxicology, Karlsruhe Institute of Technology, Adenauerring 20a, 76131, Karlsruhe, Germany

      Maria Cetraz, Sarah Schoch, Karolin Streule, Andrea Hartwig & Beate Köberle

    2. Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow, Russian Federation, 142432

      Vasily Sen & Valery Golubev

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    1. Maria Cetraz
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    Correspondence to Beate Köberle.

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    Maria Cetraz and Vasily Sen have contributed equally to the study.

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    Cetraz, M., Sen, V., Schoch, S. et al. Platinum(IV)-nitroxyl complexes as possible candidates to circumvent cisplatin resistance in RT112 bladder cancer cells. Arch Toxicol 91, 785–797 (2017). https://doi.org/10.1007/s00204-016-1754-3

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