Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo
Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo
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DOI：
10.1158/0008-5472.can-05-1042
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Holland, EC
中科院分区：
文献类型：
--
作者：
Momota, H;Nerio, E;Holland, EC
Perifosine 是一种口服 Akt 抑制剂，对人类肿瘤细胞系具有显着的细胞毒性作用，目前正在多项 H 期试验中进行测试，用于治疗主要的人类癌症。然而，哌立福辛对人类神经胶质瘤的疗效尚未确定。由于 Akt 在类似于 70% 的人类胶质母细胞瘤中被激活，我们研究了哌立福辛对培养的神经胶质细胞和体内小鼠神经胶质瘤模型的影响。在这里，我们表明，perifosine 强烈降低 Akt 和细胞外信号调节激酶 (Erk) 1/2 的磷酸化水平，诱导 G(1) 和 G(2) 细胞周期停滞，并引起小鼠神经胶质祖细胞的剂量依赖性生长抑制，其中 Akt 和/或 Ras-Erk 1/2 途径被激活。此外，由于替莫唑胺是治疗神经胶质瘤的常用口服烷化剂，我们研究了哌立福辛与替莫唑胺联合使用的效果。当两者都用于培养时，我们观察到效果增强。根据这些结果，我们将哌立福辛和替莫唑胺联合治疗小鼠血小板衍生生长因子 B 驱动的神经胶质瘤。动物研究表明，哌立福辛和替莫唑胺联合治疗比单独使用替莫唑胺治疗更有效（P < 0.01）。这些结果表明，哌立福辛是治疗Akt和Ras-Erk 1/2通路频繁激活的胶质瘤的有效药物，可能成为临床治疗胶质瘤的新候选药物。
Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase H trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in similar to 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G(1) and G(2), and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic.