Targeting multiple pathways in gliomas with stem cell and viral delivered S-TRAIL and Temozolomide.
Targeting multiple pathways in gliomas with stem cell and viral delivered S-TRAIL and Temozolomide.
复制标题
DOI：
10.1158/1535-7163.mct-08-0640
复制
发表时间：
2008-11
影响因子：
5.7
通讯作者：
Shah K
中科院分区：
文献类型：
--
作者：
Hingtgen S;Ren X;Terwilliger E;Classon M;Weissleder R;Shah K
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性杀伤肿瘤细胞。然而，其半衰期短，递送差和TRAIL抗性肿瘤细胞降低了其临床疗效。在这项研究中，我们探讨了新的交付方法是否将代表新的和有效的方法来治疗胶质瘤，如果辅助治疗与化疗剂替莫唑胺（TMZ）将提高肿瘤坏死因子相关凋亡诱导配体的细胞毒性特性的胶质瘤细胞系耐肿瘤坏死因子相关凋亡诱导配体单一疗法。我们设计了编码重组分泌型TRAIL（S-TRAIL）和生物发光-荧光标记物融合蛋白的腺相关病毒（AAV）载体，并显示AAV递送的S-TRAIL导致多种胶质瘤细胞系中不同程度的杀伤，这与半胱天冬酶-3/7激活相对应。在体内，双生物发光成像显示治疗性AAV载体直接有效递送到肿瘤块中，这诱导了肿瘤进展的显著衰减。单独用化疗剂TMZ处理胶质瘤细胞导致G2/M期细胞的显著积累，激活细胞周期检查点蛋白Chk 1，并以时间依赖性方式增加死亡受体表达。此外，用AAV-S-TRAIL或先前工程化的神经干细胞（NSC）-S-TRAIL和TMZ联合处理TRAIL抗性细胞系诱导细胞杀伤并显著上调促凋亡蛋白。这项研究阐明了将S-TRAIL递送至胶质瘤的新方法，并表明临床相关的TMZ和S-TRAIL的组合可能代表了一种新的治疗选择，其对胶质母细胞瘤患者的效力增加。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells. However, its short half-life, poor delivery and TRAIL-resistant tumor cells have diminished its clinical efficacy. In this study, we explored whether novel delivery methods will represent new and effective ways to treat gliomas and if adjuvant therapy with the chemotherapeutic-agent temozolomide (TMZ) would enhance the cytotoxic properties of TRAIL in glioma lines resistant to TRAIL monotherapy. We have engineered adeno-associated virus (AAV)-vectors encoding recombinant secreted TRAIL (S-TRAIL) and bioluminescent-fluorescent marker fusion proteins and show that AAV delivered S-TRAIL leads to varying degrees of killing in multiple glioma lines, which correspond with caspase-3/7 activation. In vivo, dual-bioluminescent imaging revealed efficient delivery of therapeutic AAV-vectors directly into the tumor mass, which induced marked attenuation of tumor progression. Treatment of glioma cells with the chemotherapeutic agent TMZ alone lead to a significant accumulation of cells in G2/M phase, activated the cell cycle checkpoint protein Chk1, and increased death receptor expression in a time-dependent manner. Furthermore, combined treatment of TRAIL-resistant cell lines with AAV-S-TRAIL or previously engineered neural stem cell (NSC)-S-TRAIL and TMZ induced cell killing and markedly upregulated pro-apoptotic proteins. This study elucidates novel means of delivering S-TRAIL to gliomas, and suggests combination of clinically relevant TMZ and S-TRAIL may represent a new therapeutic option with increased potency for glioblastoma patients.