Tumor therapy mediated by lentiviral expression of shBcl-2 and S-TRAIL
Tumor therapy mediated by lentiviral expression of shBcl-2 and S-TRAIL
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DOI：
10.1593/neo.07223
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Shah, Khalid
中科院分区：
文献类型：
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作者：
Kock, Norman;Kasmieh, Randa;Shah, Khalid
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）可选择性杀伤肿瘤细胞，与其他药物联合应用可增强肿瘤治疗效果。我们探讨了分泌型（S）TRAIL诱导的细胞凋亡和下调Bcl-2在人胶质瘤中的联合治疗作用。我们构建了一个慢病毒递送系统：1）表达短发夹（sh）RNA以下调Bcl-2和表达S-TRAIL以诱导胶质瘤细胞凋亡; 2）体外跟踪递送和体内真实的肿瘤命运。我们证明，慢病毒介导的Bcl-2和S-TRAIL诱导的细胞凋亡的同时下调导致激活的caspase-3和caspase-7的表达增加，从而导致体外胶质瘤细胞中S-TRAIL介导的细胞凋亡加速。使用表达EGFRvIII和萤火虫荧光素酶的高度恶性的人脑胶质瘤模型，我们表明，与S-TRAIL单一疗法相比，Bcl-2下调和S-TRAIL诱导的细胞凋亡的联合作用导致胶质瘤的完全根除。这些结果表明，同时触发TRAIL介导的死亡受体途径和通过shRNA下调Bcl-2导致增强的神经胶质瘤根除，并用作开发和监测用于治疗耐药性癌症的组合疗法的模板。
Tumor necrosis factor - related apoptosis-inducing ligand ( TRAIL) can selectively kill tumor cells and, in combination with other agents, could enhance tumor therapy. We explored the combined therapeutic effects of a secretable form of ( S) TRAIL-induced apoptosis and the downregulation of Bcl-2 in human gliomas. We constructed a lentiviral delivery system: 1) for the expression of short hairpin (sh) RNA to downregulate Bcl- 2 and for the expression of S-TRAIL to induce apoptosis in glioma cells; and 2) to follow delivery in vitro and the fate of tumors in real time in vivo. We demonstrate that lentiviral- mediated simultaneous downregulation of Bcl- 2 and S-TRAIL-induced apoptosis leads to an increased expression of activated caspase- 3 and caspase- 7, thus resulting in accelerated S-TRAIL-mediated apoptosis in glioma cells in vitro. Using a highly malignant human glioma model expressing EGFRvIII and firefly luciferase, we show that the combined effect of Bcl-2 downregulation and S-TRAIL-induced apoptosis results in complete eradication of gliomas compared to S-TRAIL monotherapy. These results show that simultaneous triggering of TRAIL-mediated death receptor pathway and downregulation of Bcl-2 by shRNA leads to enhanced eradication of gliomas and serves as a template in developing and monitoring combination therapies for the treatment of drug- resistant cancers.