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Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing’s sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

SIRT1-activating compounds (STACs) may have potential in the management of cancer. However, the best-studied STAC, the naturally occurring compound resveratrol, is reported to have contradictory effects in combination chemotherapy regimens: It has been shown both to increase and to decrease the action of anticancer agents. To shed more light on this issue, we comparatively investigated the impact of resveratrol and the synthetic STAC SRT1720 on the responsiveness of Ewing’s sarcoma (ES) cells to the chemotherapeutic drugs etoposide and vincristine.

Methods

Because the effects of STACs can depend on the functionality of the tumor suppressor protein p53, we used three ES cell lines differing in their p53 status, i.e., wild-type p53 WE-68 cells, mutant p53 SK-ES-1 cells and p53 null SK-N-MC cells. Single agent and combination therapy effects were assessed by flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization, by measuring caspase 3/7 activity and by gene expression profiling.

Results

When applied as single agents, both STACs were effective in ES cells irrespective of their p53 status. Strikingly, however, when applied in conjunction with cytostatic agents, the STACs displayed reverse effects: SRT1720 largely enhanced etoposide- and vincristine-induced cell death, while resveratrol inhibited it. Combination index analyses validated the antipodal impact of the STACs on the effectiveness of the chemotherapeutics.

Conclusion

These findings suggest that the synthetic STAC SRT1720 may be useful to enhance the efficacy of anticancer therapy in ES. But they also suggest that the dietary intake of the natural STAC resveratrol may be detrimental during chemotherapy of ES.

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Acknowledgments

Work in the group of OHK is supported by the Deutsche Krebshilfe (#110909 and #110125) and the Wilhelm Sander-Stiftung (#2010.078.2).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Children’s Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany

    Jürgen Sonnemann, Melanie Kahl, Priyanka M. Siranjeevi, Annelie Blumrich, Lisa Blümel, Sabine Becker, Susan Wittig, René Winkler & James F. Beck

  2. Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131, Mainz, Germany

    Oliver H. Krämer

  3. Klinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Kochstr. 2, 07745, Jena, Germany

    Jürgen Sonnemann

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  1. Jürgen Sonnemann
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  2. Melanie Kahl
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  3. Priyanka M. Siranjeevi
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  4. Annelie Blumrich
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  5. Lisa Blümel
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  6. Sabine Becker
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  7. Susan Wittig
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  8. René Winkler
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  9. Oliver H. Krämer
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  10. James F. Beck
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Correspondence to Jürgen Sonnemann.

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Sonnemann, J., Kahl, M., Siranjeevi, P.M. et al. Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing’s sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity. J Cancer Res Clin Oncol 142, 17–26 (2016). https://doi.org/10.1007/s00432-015-1994-2

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