Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells
Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells
复制标题
DOI：
10.1182/blood-2005-08-3434
复制
发表时间：
2006-05-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Hideshima, Teru;Catley, Laurence;Anderson, Kenneth C.
Perifosine是一种合成的新型烷基磷脂，是一类靶向细胞膜并抑制Akt活化的新型抗肿瘤药物。本研究表明，在多发性骨髓瘤（MM）细胞中，Akt的基线磷酸化被酪氨酸[十八烷基-（1,1-d甲基-胡椒-4-基）-磷酸]以时间和剂量依赖的方式完全抑制，而不抑制磷酸肌醇依赖性蛋白激酶1的磷酸化。Perifosine诱导MM细胞系和患者MM细胞对常规治疗药物产生显著的细胞毒性。对外周血单核细胞不产生细胞毒性。外源性白细胞介素-6 （IL-6）和胰岛素样生长因子1 （IGF-1）都不能克服perifosine诱导的细胞毒性。重要的是，Perifosine甚至可以诱导粘附在骨髓基质细胞上的MM细胞凋亡。Perifosine触发c-Jun n -末端激酶（JNK）激活，随后caspase-8/9和聚（ADP）核糖聚合酶裂解。抑制JNK可消除perifosine诱导的细胞毒性，提示JNK在perifosine诱导的细胞凋亡中起重要作用。有趣的是，胞外信号相关激酶（ERK）的磷酸化被酪氨酸增加；相反，MEK抑制剂协同增强perifosine诱导的MM细胞毒性。此外，洋槐碱增强了地塞米松、阿霉素、美法兰和硼替佐米诱导的MM细胞毒性。最后，在人浆细胞瘤小鼠模型中，perifosine显示出显著的抗肿瘤活性，与肿瘤细胞中Akt磷酸化的下调有关。综上所述，我们的数据为缬草碱改善MM患者预后的临床试验提供了理论依据。
Perifosine is a synthetic novel alkylphos-pholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in multiple myeloma (MM) cells is completely inhibited by perifosine [octadecyl-(1,1-d imethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant-to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mono-nuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers c-Jun N-terminal kinase (JNK) activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis. Interestingly, phosphorylation of extracellular signal-related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor syn-ergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM.