Combination of an allosteric Akt Inhibitor MK-2206 with etoposide or rapamycin enhances the antitumor growth effect in neuroblastoma.
Combination of an allosteric Akt Inhibitor MK-2206 with etoposide or rapamycin enhances the antitumor growth effect in neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-11-3321
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发表时间：
2012-07-01
期刊：
影响因子：
--
通讯作者：
Thiele CJ
中科院分区：
文献类型：
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作者：
Li Z;Yan S;Attayan N;Ramalingam S;Thiele CJ
Akt的激活是神经母细胞瘤(NB)患者无事件或总体生存率下降的标志。MK-2206是一种新型变构Akt抑制剂，目前正在成人癌症的临床试验中进行测试。在本研究中，我们评价了MK-2206单独或与依托泊苷或雷帕霉素合用对肿瘤生长和小鼠存活的影响。用MTS法检测MK-2206对8株NB细胞的抗增殖作用。测定caspase3/7活性、细胞周期分析和活性氧(ROS)生成。观察MK-2206与依托泊苷或雷帕霉素合用的体内外疗效。用Western blotting检测NB细胞和肿瘤组织中AKT的磷酸化。在体外，MK-2206处理抑制了NB细胞的增殖，并伴随着细胞株选择性的G1期细胞周期停滞或ROS的产生。MK-2206与依托泊苷通过caspase依赖的细胞凋亡在4株受试的NB细胞中具有协同作用，而MK-2206与雷帕霉素联合作用则通过产生ROS来增强对细胞生长的抑制作用。在体内，MK-2206单独使用会抑制肿瘤中Akt的磷酸化，从而抑制肿瘤中Akt的磷酸化，从而减少肿瘤生长并增加小鼠的存活率。与单独应用MK-2206相比，MK-2206与依托泊苷或雷帕霉素联合应用可显著抑制肿瘤生长，提高小鼠存活率。MK-2206抑制AKT可增强依托泊苷或雷帕霉素的药效。我们的研究支持MK-2206联合常规细胞毒治疗或联合雷帕霉素治疗高危NB患者的未来临床评估。
Activation of Akt is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. MK-2206, a novel allosteric Akt inhibitor, is now tested in clinical trials in adult cancers. In this study, effect of MK-2206 on tumor growth and murine survival, alone or in combination with etoposide or rapamycin was evaluated. The anti-cell proliferation effect of MK-2206 was tested in eight NB cell lines by MTS assay. Caspase 3/7 activity, cell cycle analysis and reactive oxygen species (ROS) production were determined. Effect of MK-2206 combined with etoposide or rapamycin was evaluated in vitro and in vivo. Akt phosphorylation was measured by Western blotting in NB cells and tumors. In vitro, MK-2206 treatment inhibited NB cell proliferation which was accompanied by a cell line selective G1 arrest of cell cycle or production of ROS. A synergistic effect between MK-2206 and etoposide was detected in 4 tested NB cell lines via caspase-dependent apoptosis, while increased inhibition of cell growth induced by combination of MK-2206 and rapamycin was mediated by ROS production. In vivo, MK-2206 alone decreased tumor growth and increased murine survival at dose which inhibited Akt phosphorylation in tumors. MK-2206, in combination with etoposide or rapamycin, caused a significant decrease in tumor growth and increase of murine survival compared to MK-2206 alone. Akt inhibition by MK-2206 increased the efficacy of etoposide or rapamycin. Our study supports future clinical evaluation of MK-2206 in combination with conventional cytotoxic therapy or with rapamycin in high-risk NB patients.