MicroRNA-21 knockdown disrupts glioma growth In vivo and displays synergistic cytotoxicity with neural precursor cell-delivered S-TRAIL in human gliomas

被引:323
作者
Corsten, Maarten F.
Miranda, Rafael
Kasmieh, Randa
Krichevsky, Anna M.
Weissleder, Ralph
Shah, Khalid [1 ]
机构
[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging, Charlestown, MA 02129 USA
[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA USA
关键词
D O I
10.1158/0008-5472.CAN-07-1045
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor-related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21-treated gliomas subjected to the presence of NIPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies.
引用
收藏
页码:8994 / 9000
页数:7
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