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Mitochondrial Mode of Action of a Thymidine-Based Cisplatin Analogue Breaks Resistance in Cancer Cells

Authors

  • Liliane A. Onambele,

    1. Children's Hospital of the City of Cologne, Amsterdamerstr. 59, 507335 Cologne (Germany), Fax: (+49) 3641948202
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  • Dr. Daniel Koth,

    1. Laboratory for Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena (Germany), Fax: (+49) 3641948202
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  • Dr. Justyna A. Czaplewska,

    1. Laboratory for Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena (Germany), Fax: (+49) 3641948202
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  • Prof. Ulrich S. Schubert,

    1. Laboratory for Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena (Germany), Fax: (+49) 3641948202
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  • Dr. Helmar Görls,

    1. Institute for Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena, Lessingstr. 8, 07743 Jena (Germany)
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  • Prof. Shigenobu Yano,

    1. Nara Institute of Science and Technology (NAIST), 8916-5, Takayama-cho, Ikoma, Nara 630-0192 (Japan)
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  • Dr. Makoto Obata,

    1. Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Takeda 4-4-37, Kofu 400-8510 (Japan)
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  • Dr. Michael Gottschaldt,

    Corresponding author
    1. Laboratory for Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena (Germany), Fax: (+49) 3641948202
    • Laboratory for Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena (Germany), Fax: (+49) 3641948202
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  • Dr. Dr. Aram Prokop

    Corresponding author
    1. Children's Hospital of the City of Cologne, Amsterdamerstr. 59, 507335 Cologne (Germany), Fax: (+49) 3641948202
    • Children's Hospital of the City of Cologne, Amsterdamerstr. 59, 507335 Cologne (Germany), Fax: (+49) 3641948202
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Abstract

Abstract: Cisplatin analogue complexes with platinum(II) and palladium(II) starting from 3′,5′-diamino-3′,5′-dideoxy-thymidines were synthesized, both with the D-erythro- and D-threo configurations. Complexes of the general formula [MCl2L] were obtained and characterized. NMR spectroscopic measurements and single crystal X-ray structure analysis showed that the metal centers are coordinated to the ligands by the amino groups in 3′- and 5′-positions and not through the thymine moiety. All ligands and complexes showed no significant in vitro activities except thymiplatin (cis-dichloro(3′,5′-diamino-3′,5′-dideoxy-D-threo-thymidine)platinum(II)). Detailed in vitro studies on the apoptosis pathway in lymphoma (BJAB), leukemia (NALM-6), and melanoma cells (Mel-HO) as well as on transfected or resistant cell lines were carried out. Thymiplatin significantly induced an apoptotic response, which was found to be associated with the loss of mitochondrial membrane potential and with caspase activation. The activity was shown to be independent of Fas-associated protein with death domain (FADD), but dependent on Bcl-2 expression. As a consequence, for thymiplatin a mitochondrial mode of action could be assigned. Moreover, the compound showed activity in cells resistant to common drugs, such as daunorubicin and vincristin, and showed synergistic effects with doxorubicin, vincristin, cytarabin, and daunorubicin.

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