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

• Verfasst von: Tagscherer, Katrin [VerfasserIn]
• Verfasst von: Faßl, Anne [VerfasserIn]
• Verfasst von: Sinkovic, Tabea [VerfasserIn]
• Verfasst von: Combs, Stephanie [VerfasserIn]
• Verfasst von: Roth, Wilfried [VerfasserIn]
• Titel: p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737
• Verf.angabe: Katrin E. Tagscherer, Anne Fassl, Tabea Sinkovic, Stephanie E. Combs, Wilfried Roth
• Jahr: 2012
• Umfang: 13 S.
• Fussnoten: Published online: 15 October 2011 ; Gesehen am 03.07.2018
• Titel Quelle: Enthalten in: Apoptosis
• Ort Quelle: Dordrecht [u.a.] : Springer Science + Business Media B.V, 1996
• Jahr Quelle: 2012
• Band/Heft Quelle: 17(2012), 2, Seite 187-199
• ISSN Quelle: 1573-675X
• DOI: doi:10.1007/s10495-011-0664-3
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1577205596

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.