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The effect of the triazene compound CT913 on ovarian cancer cells in vitro and its synergistic interaction with the PARP-inhibitor olaparib

  • Author Footnotes
    1 These authors contributed equally to the underlying study.
    Catharina Wichmann
    Footnotes
    1 These authors contributed equally to the underlying study.
    Affiliations
    Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Author Footnotes
    1 These authors contributed equally to the underlying study.
    Daniel Martin Klotz
    Footnotes
    1 These authors contributed equally to the underlying study.
    Affiliations
    Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Hans-Joachim Zeiler
    Affiliations
    Creative Therapeutics GmbH, Wuppertal, Germany
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  • Ralf Axel Hilger
    Affiliations
    University Hospital Essen, Department of Medical Oncology, West German Cancer Center, Essen, Germany
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  • Konrad Grützmann
    Affiliations
    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Core Unit for Molecular Tumor Diagnostics (CMTD), Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU, Dresden, Germany
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  • Alexander Krüger
    Affiliations
    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Core Unit for Molecular Tumor Diagnostics (CMTD), Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU, Dresden, Germany
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  • Daniela Aust
    Affiliations
    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Core Unit for Molecular Tumor Diagnostics (CMTD), Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU, Dresden, Germany
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  • Pauline Wimberger
    Affiliations
    Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Jan Dominik Kuhlmann
    Correspondence
    Corresponding author at: Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
    Affiliations
    Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Author Footnotes
    1 These authors contributed equally to the underlying study.
Published:September 23, 2020DOI:https://doi.org/10.1016/j.ygyno.2020.09.018

      Highlights

      • we analysed the effect of a novel triazene (CT913) on ovarian cancer cells and describe their interaction with olaparib.
      • CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells.
      • CT913 downregulated a variety of transcripts involved in DNA-repair pathways, such as homologous recombination repair (HR).
      • CT913 showed a synergistic interaction with olaparib, independently of BRCA-1 mutational status.
      • This is the first study, suggesting the novel triazene drug CT913 for extending the therapeutic spectrum of PARPi.

      Abstract

      Objectives

      Extending the therapeutic spectrum of PARP-inhibitors (PARPi) beyond BRCA1-deficiency and/or overcoming PARPi-resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a possible strategy for defining new therapeutic standards. In this study, we analyzed the therapeutic effect of novel triazene derivatives, including the drug CT913 and its metabolite CT913-M1 on ovarian cancer cells and describe their interaction with the PARPi olaparib.

      Methods

      In vitro assays for drug characterization including RNA-Seq were applied in a selected panel of ovarian cancer cell lines.

      Results

      CT913 treatment conferred a dose-dependent reduction of cell viability in a set of platinum-sensitive and platinum-resistant ovarian cancer cell lines with an IC50 in the higher micromolar range (553–1083 μM), whereas its metabolite CT913-M1 was up to 69-fold more potent, especially among long-term treatment (IC50 range: 8–138 μM). Neither of the drugs sensitized for cisplatin. CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells, indicating that its effect is augmented by a deficiency in homologous recombination repair (HR). Furthermore, CT913 showed a synergistic interaction with olaparib, independently of BRCA1 mutational status. CT913 strongly induced CDKN1A transcription, suggesting cell cycle arrest as an early response to this drug. It moreover downregulated a variety of transcripts involved in DNA-repair pathways.

      Conclusions

      This is the first study, suggesting the novel triazene drug CT913 as enhancer drug for extending the therapeutic spectrum of PARPi.

      Graphical abstract

      Abbreviations:

      PARPi (poly(ADP-ribose)-polymerase inhibition or inhibitor), IC50 (half maximal inhibitory concentration), HR (homologuous recombination repair), MMR (mismatch repair), NER (nucleotide exision repair), PFS (progression-free survival), OS (overall survival), MGMT (O(6)-methyl-DNA-methyltransferase), CP (cisplatin), CI (combination index), GEO (Gene Expression Omnibus), DEG (differentially regulated gene), Ahr (arylhydrocarbon receptor)

      Keywords

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