Akt down-modulation induces apoptosis of human prostate cancer cells and synergizes with EGFR tyrosine kinase inhibitors
Akt down-modulation induces apoptosis of human prostate cancer cells and synergizes with EGFR tyrosine kinase inhibitors
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DOI：
10.1002/pros.20757
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发表时间：
2008-06-15
期刊：
影响因子：
2.8
通讯作者：
Bologna, Mauro
中科院分区：
文献类型：
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作者：
Festuccia, Claudio;Gravina, Giovanni Luca;Bologna, Mauro
背景。 PTEN 是一种特性良好的肿瘤抑制因子，可通过调节 PI3K/Akt 通路来负向调节细胞生长和存活。在本文中，我们研究了 PI3K/Akt 抑制剂哌立福辛对人前列腺癌 (PCa) 细胞的影响，分析细胞增殖、凋亡以及与 EGFR 抑制剂的协同作用。结果。临床可达到的哌立福辛浓度以及 Akt 基因敲低可诱导 PTEN 缺陷 PCa 细胞出现 G0/G1 期停滞和细胞凋亡。虽然PTEN的引入能够恢复Akt活性的控制并减少细胞增殖，但单独操作PTEN基因并不能影响细胞凋亡。当 EGF 增强 Akt 活性时，Perifosine 也在 PTEN 阳性细胞中诱导细胞凋亡程序，这表明该药物可以与 EGFR 抑制剂联合使用。厄洛替尼和药物或分子 Akt 敲低之间的联合治疗确实显示出协同效应。这是首次证明抗 Akt 活性的药理学化合物可以恢复针对 PCa 中 EGFR 抑制剂的功效，并且具有重要的治疗效果，因为 EGFR 抑制剂已证明对 PCa 患者的有效性非常低。结论。综上所述，我们的数据对于晚期前列腺肿瘤的治疗具有重要的临床意义。然而，有必要对晚期 PC 的联合治疗进行进一步研究。
BACKGROUND. PTEN is a well-characterized tumor suppressor that negatively regulates cell growth and survival through the modulation of PI3K/Akt pathway.METHODS. In this paper, we investigated the effects of an PI3K/Akt inhibitor, perifosine, in human prostate cancer (PCa) cells analyzing cell proliferation, apoptosis, and the synergy with EGFR inhibitors.RESULTS. Clinically achievable concentrations of perifosine, as well as Akt gene knockdown, induced a G0/G1 arrest and apoptosis in PTEN defective PCa cells. Although PTEN introduction was able to restore the control of Akt activity and to reduce cell proliferation, the manipulation of PTEN gene was not able alone to influence apoptosis. Perifosine induced apoptotic program also in PTEN positive cells when Akt activity was augmented by EGF suggesting the possibility that this drug could be used in combination with EGFR inhibitors. The combination treatment between erlotinib and pharmacological or molecular Akt knockdown, indeed, showed synergistic effects. This is the first demonstration that a pharmacological compound against Akt activity can restore the efficacy against EGFR inhibitors in PCa and has important therapeutic fallout since EGFR inhibitors have demonstrated very low effectiveness in PCa patients.CONCLUSIONS. Taken together our data have an important clinical relevance in the treatment of advanced prostate tumors. However, further studies in the setting of combination therapies in advanced PCas are necessary.