The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism
The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism
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DOI：
10.1038/leu.2008.79
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发表时间：
2008-06-01
期刊：
影响因子：
11.4
通讯作者：
Martelli, A. M.
中科院分区：
文献类型：
--
作者：
Chiarini, F.;Del Sole, M.;Martelli, A. M.
癌症化疗成功的一个重要障碍是多药耐药性的发生，在许多情况下，这是由于膜转运蛋白，如170-kDa的P-糖蛋白（P-gp）的过表达。此外，已知磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路的上调在耐药性中起重要作用，并且与许多不同癌症的侵袭性有关，包括T-急性淋巴细胞白血病（T-ALL）。我们研究了新型Akt抑制剂哌立福新（一种合成烷基磷脂）对人T-ALL CEM细胞（CEM-R）的治疗潜力，其特征在于P-gp的过表达和PI 3 K/Akt网络的组成性上调。哌立福新处理通过CEM-R细胞的凋亡诱导死亡。凋亡的特征是caspase激活，Bid切割和细胞色素c从线粒体释放。哌立福辛的促凋亡作用部分依赖于Fas/FasL相互作用和c-Jun氨基末端激酶（JNK）激活，以及脂筏的完整性。哌立福新下调P-gp mRNA和蛋白表达，这种作用需要JNK活性的参与。我们的研究结果表明，哌立福新是一种有前途的治疗药物，用于治疗以PI 3 K/Akt生存通路上调和P-gp过表达为特征的T-ALL病例。
A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH(2)-terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.