Translational Radiobiology and Radiooncology Research Laboratory, Department of Radiotherapy, Charité Campus Mitte, Charité Campus Virchow-Klinikum, Charité Universitätsmedizin-Berlin, Berlin, Germany.
Mol Cancer Ther. 2010 Feb;9(2):480-8. doi: 10.1158/1535-7163.MCT-09-0498. Epub 2010 Jan 26.
PTEN mutations are frequently found in malignant glioma and can result in activated phosphatidylinositol-3-kinase/Akt survival signaling associated with resistance to radiotherapy. Strategies to interfere with aberrant PI3K/Akt activity are therefore being developed to improve the therapeutic efficacy of radiotherapy in patients with malignant glioma. The methylxanthine caffeine has been described as a PI3K inhibitor and is also known to sensitize cells to ionizing radiation. However, a direct association between these two caffeine-mediated effects has not been reported yet. Therefore, we asked whether caffeine or its derivative pentoxifylline differentially affect the radiosensitivity of malignant gliomas with different PTEN status. As models, we used the radiosensitive EA14 malignant glioma cell line containing wild-type PTEN and the radioresistant U87MG malignant glioma cell line harboring mutant PTEN. Our study revealed that caffeine and pentoxifylline radiosensitized PTEN-deficient but not PTEN-proficient glioma cells. Radiosensitization of PTEN-deficient U87MG cells by caffeine was significantly correlated with the activation of the G(1) DNA damage checkpoint that occurred independently of de novo synthesis of p53 and p21. The p53 independency was also confirmed by a significant caffeine-mediated radiosensitization of the glioma cell lines T98G and U373MG that are deficient for both PTEN and p53. Furthermore, caffeine-mediated radiosensitization was associated with the inhibition of Akt hyperphosphorylation in PTEN-deficient cells to a level comparable with PTEN-proficient cells. Our data suggest that the methylxanthine caffeine or its derivative pentoxifylline are promising candidate drugs for the radiosensitization of glioma cells particularly with PTEN mutations.
PTEN 突变在恶性神经胶质瘤中经常发生，并可能导致与放疗抵抗相关的激活磷脂酰肌醇-3-激酶/ Akt 存活信号。因此，正在开发干扰异常 PI3K/Akt 活性的策略，以提高恶性神经胶质瘤患者的放疗疗效。甲基黄嘌呤咖啡因已被描述为 PI3K 抑制剂，并且还已知可使细胞对电离辐射敏感。然而，尚未报道这两种咖啡因介导的作用之间的直接关联。因此，我们询问咖啡因或其衍生物己酮可可碱是否会以不同的方式影响具有不同 PTEN 状态的恶性神经胶质瘤的放射敏感性。作为模型，我们使用了含有野生型 PTEN 的放射敏感 EA14 恶性神经胶质瘤细胞系和含有突变型 PTEN 的放射抗性 U87MG 恶性神经胶质瘤细胞系。我们的研究表明，咖啡因和己酮可可碱放射增敏了 PTEN 缺失但不 PTEN 丰富的神经胶质瘤细胞。咖啡因对 PTEN 缺失的 U87MG 细胞的放射增敏作用与 G1 DNA 损伤检查点的激活显著相关，该激活独立于 p53 和 p21 的从头合成。p53 独立性也通过对同时缺乏 PTEN 和 p53 的神经胶质瘤细胞系 T98G 和 U373MG 的显著咖啡因介导的放射增敏得到证实。此外，咖啡因介导的放射增敏与 Akt 过度磷酸化的抑制有关，在 PTEN 缺失的细胞中，该抑制作用可与 PTEN 丰富的细胞相当。我们的数据表明，甲基黄嘌呤咖啡因或其衍生物己酮可可碱是放射增敏神经胶质瘤细胞，特别是具有 PTEN 突变的神经胶质瘤细胞的有前途的候选药物。
