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Selected ellipticine derivatives, known to target topoisomerase II, suppress the alternative lengthening of telomere (ALT) pathway in telomerase–negative cells

  • Original Article – Cancer Research
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Abstract

Background

DNA topoisomerase and telomerase enzymes are popular targets of several anti-tumor drugs. Smooth proceeding of telomeric recombination requires Topoisomerase II (Top2), which is involved in telomere-telomere recombination through functioning in relaxation of positive supercoils among the cells adopting telomerase-independent Alternative lengthening of telomere (ALT) pathway. Most of the inhibitors reported so far have been designed to targetsolely telomerase-positive cells, which can potentially lead to therapeutic failure because tumor cells treated with telomerase inhibitors can activate the ALT pathway for telomere maintenance. Knowing that ALT cells are more sensitive against a Top2 inhibitor, ICRF-93 agent, compared to telomerase-positive cells, we analyzed two selected ellipticine derivatives that we recently reported as TopII-targeting compounds, to assess their effects on the formation of DNA breaks and suppression of ALT pathway.

Methods

Cell viability, Comet, C-Circle assays, dot blot, immunofluorescence staining, and telomere fluorescence in situ hybridization (FISH) staining were used for determining the effect of the compounds on ALT status of tumor cells.

Results and conclusions

Treatment of ALT cells with ellipticine derivatives resulted in the formation of DNA breaks and suppression of ALT-associated phenotypes in vitro. Our results will contribute to the development of therapeutic strategies combining telomerase and ALT pathway inhibitors.

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Acknowledgements

This research was supported by Grant 115Z349 (Z.T. and S.Z.) from the Turkish Scientific and Technical Research Assembly. The cell lines used in this study were provided by Drs. Shu-Chun Teng and Tsai-Kun Li (College of Medicine, National Taiwan University, Taipei, Taiwan).

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Authors and Affiliations

  1. Department of Molecular Biology, University of Geneva, CH-1211, Geneva 4, Switzerland

    Sevil Zencir

  2. Department of Medical Biology, Faculty of Medicine, Pamukkale University, 20020, Denizli, Turkey

    Sevil Zencir

  3. Department of Microbiology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Meng-Hsun Hsieh, Joel-Sean Hsu, Guan-Ling Chou, Tsai-Kun Li & Shu-Chun Teng

  4. Department of Chemistry, Faculty of Science, Dokuz Eylul University, 35160, Izmir, Turkey

    Yavuz Ergun

  5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, 35100, Izmir, Turkey

    Zeki Topcu

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  1. Sevil Zencir
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  2. Meng-Hsun Hsieh
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  3. Joel-Sean Hsu
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  8. Zeki Topcu
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Correspondence to Sevil Zencir.

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Zencir, S., Hsieh, MH., Hsu, JS. et al. Selected ellipticine derivatives, known to target topoisomerase II, suppress the alternative lengthening of telomere (ALT) pathway in telomerase–negative cells. J Cancer Res Clin Oncol 146, 1671–1676 (2020). https://doi.org/10.1007/s00432-020-03213-x

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