title: p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737.
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.
authors: Molecular Tumor Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors: Katrin E
authors: KE
authors: Tagscherer
authors: Anne
authors: A
authors: Fassl
authors: Tabea
authors: T
authors: Sinkovic
authors: Stephanie E
authors: SE
authors: Combs
authors: Wilfried
authors: W
authors: Roth
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011839:Radiation, Ionizing; D013449:Sulfonamides / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D050759:Cyclin-Dependent Kinase Inhibitor p21; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein