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p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737

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Abstract

Treatment with the Bcl-2/Bcl-XL inhibitor ABT-737 is a promising novel strategy to therapeutically induce apoptotic cell death in malignant tumors such as glioblastomas. Although many studies have demonstrated that ABT-737 acts synergistically with chemotherapeutic drugs, the possibility of a combined treatment with ionizing radiation (IR) and ABT-737 has not yet been thoroughly investigated. Similarly, the relationship between p53 function and the pro-apoptotic effects of ABT-737 are still obscure. Here, we demonstrate that IR and ABT-737 synergistically induce apoptosis in glioblastoma cells. The sensitivity to ABT-737-mediated cell death is significantly increased by the IR-dependent accumulation of cells in the G2/M cell cycle phase. Wild type p53 function inhibits the efficacy of a combined IR and ABT-737 treatment via a p21-dependent G1 cell cycle arrest. Moreover, mutant as well as wild type p53 counteract the pro-apoptotic activity of ABT-737 by maintaining the expression levels of the Mcl-1 protein. Thus, p53 regulates the sensitivity to ABT-737 of glioblastoma cells. Our results warrant a further evaluation of a novel combination therapy using IR and ABT-737. The efficacy of such a therapy could be substantially enhanced by Mcl-1-lowering strategies.

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Abbreviations

IR:

Ionizing radiation

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Acknowledgments

This work was supported by grants from the Dietmar-Hopp Foundation (St. Leon-Rot, Germany) to W.R. and S.E.C. and from the Federal Ministry of Education and Research (BMBF) to W.R. (NGFNplus Brain Tumor Network; grant number 01GS0883). We thank Jutta Richter and Martina Keith for expert technical assistance.

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Authors and Affiliations

  1. Molecular Tumor Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Katrin E. Tagscherer, Anne Fassl, Tabea Sinkovic & Wilfried Roth

  2. Department of Radiotherapy, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Tabea Sinkovic & Stephanie E. Combs

  3. Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany

    Wilfried Roth

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  1. Katrin E. Tagscherer
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Correspondence to Wilfried Roth.

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Tagscherer, K.E., Fassl, A., Sinkovic, T. et al. p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737. Apoptosis 17, 187–199 (2012). https://doi.org/10.1007/s10495-011-0664-3

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