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Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis

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Summary

Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the anti-proliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC50 values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.

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Authors and Affiliations

  1. University of Minnesota Medical School, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, 55414, USA

    Ahmad Raza, Blake A. Jacobson, Manish R. Patel, Joe Jay-Dixon & Robert Arthur Kratzke

  2. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, 55414, USA

    Hiroshi Hiasa

  3. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55414, USA

    Adam Benoit & David M. Ferguson

  4. Center for Drug Design, University of Minnesota, Minneapolis, MN, 55414, USA

    David M. Ferguson

Authors
  1. Ahmad Raza
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  2. Blake A. Jacobson
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  3. Adam Benoit
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  4. Manish R. Patel
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  5. Joe Jay-Dixon
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  6. Hiroshi Hiasa
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  7. David M. Ferguson
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  8. Robert Arthur Kratzke
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Corresponding authors

Correspondence to David M. Ferguson or Robert Arthur Kratzke.

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Raza, A., Jacobson, B.A., Benoit, A. et al. Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis. Invest New Drugs 30, 1443–1448 (2012). https://doi.org/10.1007/s10637-011-9720-7

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  • DOI: https://doi.org/10.1007/s10637-011-9720-7

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