Molecular Tumor Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Apoptosis. 2012 Feb;17(2):187-99. doi: 10.1007/s10495-011-0664-3.
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.
用 Bcl-2/Bcl-XL 抑制剂 ABT-737 治疗是一种很有前途的新策略，可以在恶性肿瘤（如脑胶质瘤）中诱导细胞凋亡。虽然许多研究表明 ABT-737 与化疗药物具有协同作用，但与电离辐射（IR）联合治疗的可能性尚未得到彻底研究。同样，p53 功能与 ABT-737 的促凋亡作用之间的关系仍然不清楚。在这里，我们证明 IR 和 ABT-737 协同诱导脑胶质瘤细胞凋亡。IR 依赖性细胞在 G2/M 细胞周期中积累，显著增加了对 ABT-737 介导的细胞死亡的敏感性。野生型 p53 功能通过 p21 依赖性 G1 细胞周期阻滞抑制联合 IR 和 ABT-737 治疗的疗效。此外，突变型和野生型 p53 通过维持 Mcl-1 蛋白的表达水平来抵抗 ABT-737 的促凋亡活性。因此，p53 调节脑胶质瘤细胞对 ABT-737 的敏感性。我们的结果证明了使用 IR 和 ABT-737 的新型联合治疗的进一步评估是合理的。通过降低 Mcl-1 水平的策略，可以显著提高这种治疗的疗效。
