Elrod Heath A, Lin Yi-Dan, Yue Ping, Wang Xuerong, Lonial Sagar, Khuri Fadlo R, Sun Shi-Yong
Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road Northeast, C3088, Atlanta, GA 30322, USA.
Mol Cancer Ther. 2007 Jul;6(7):2029-38. doi: 10.1158/1535-7163.MCT-07-0004. Epub 2007 Jun 29.
The Akt inhibitor, perifosine, is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of cancer. The mechanisms by which perifosine exerts its antitumor effects, including the induction of apoptosis, are not well understood. The current study focused on the effects of perifosine on the induction of apoptosis and its underlying mechanisms in human non-small cell lung cancer (NSCLC) cells. Perifosine, at clinically achievable concentration ranges of 10 to 15 micromol/L, effectively inhibited the growth and induced apoptosis of NSCLC cells. Perifosine inhibited Akt phosphorylation and reduced the levels of total Akt. Importantly, enforced activation of Akt attenuated perifosine-induced apoptosis. These results indicate that Akt inhibition is necessary for perifosine-induced apoptosis. Despite the activation of both caspase-8 and caspase-9, perifosine strikingly induced the expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, death receptor 5, and down-regulated cellular FLICE-inhibitory protein (c-FLIP), an endogenous inhibitor of the extrinsic apoptotic pathway, with limited modulatory effects on the expression of other genes including Bcl-2, Bcl-X(L), PUMA, and survivin. Silencing of either caspase-8 or death receptor 5 attenuated perifosine-induced apoptosis. Consistently, further down-regulation of c-FLIP expression with c-FLIP small interfering RNA sensitized cells to perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP conferred resistance to perifosine. Collectively, these data indicate that activation of the extrinsic apoptotic pathway plays a critical role in perifosine-induced apoptosis. Moreover, perifosine cooperates with TRAIL to enhance the induction of apoptosis in human NSCLC cells, thus warranting future in vivo and clinical evaluation of perifosine in combination with TRAIL in the treatment of NSCLC.
Akt抑制剂哌立福辛是一种具有抗肿瘤特性的烷基磷脂，目前正处于针对各类癌症的II期临床试验阶段。哌立福辛发挥其抗肿瘤作用的机制，包括诱导细胞凋亡，目前尚未完全明确。当前研究聚焦于哌立福辛对人非小细胞肺癌（NSCLC）细胞诱导凋亡的影响及其潜在机制。在临床可达到的10至15微摩尔/升浓度范围内，哌立福辛有效抑制了NSCLC细胞的生长并诱导其凋亡。哌立福辛抑制Akt磷酸化并降低总Akt水平。重要的是，Akt的强制激活减弱了哌立福辛诱导的凋亡。这些结果表明，Akt抑制对于哌立福辛诱导的凋亡是必要的。尽管半胱天冬酶-8和半胱天冬酶-9均被激活，但哌立福辛显著诱导肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体死亡受体5的表达，并下调细胞FLICE抑制蛋白（c-FLIP），即外源性凋亡途径的内源性抑制剂，而对包括Bcl-2、Bcl-X(L)、PUMA和生存素在内的其他基因的表达具有有限的调节作用。沉默半胱天冬酶-8或死亡受体5均可减弱哌立福辛诱导的凋亡。同样，用c-FLIP小干扰RNA进一步下调c-FLIP表达可使细胞对哌立福辛诱导的凋亡敏感，而异位c-FLIP的强制过表达则赋予细胞对哌立福辛的抗性。总体而言，这些数据表明外源性凋亡途径的激活在哌立福辛诱导的凋亡中起关键作用。此外，哌立福辛与TRAIL协同作用可增强对人NSCLC细胞凋亡的诱导，从而有必要在未来对哌立福辛与TRAIL联合治疗NSCLC进行体内和临床评估。
