p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737
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 combin...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2012
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| In: |
Apoptosis
Year: 2012, Jahrgang: 17, Heft: 2, Pages: 187-199 |
| ISSN: | 1573-675X |
| DOI: | 10.1007/s10495-011-0664-3 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1007/s10495-011-0664-3 Verlag, Volltext: https://link.springer.com/article/10.1007/s10495-011-0664-3 
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| Verfasserangaben: | Katrin E. Tagscherer, Anne Fassl, Tabea Sinkovic, Stephanie E. Combs, Wilfried Roth |
| Zusammenfassung: | 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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| Beschreibung: | Published online: 15 October 2011 Gesehen am 03.07.2018 |
| Beschreibung: | Online Resource |
| ISSN: | 1573-675X |
| DOI: | 10.1007/s10495-011-0664-3 |