Synergistic Cytotoxicity with Neural Precursor In vivo MicroRNA-21 Knockdown Disrupts Glioma Growth

Abstract

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 NPC-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. [Cancer Res 2007;67(19):8994–9000]

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Cite this paper

@inproceedings{Corsten2007SynergisticCW, title={Synergistic Cytotoxicity with Neural Precursor In vivo MicroRNA-21 Knockdown Disrupts Glioma Growth}, author={Maarten F. Corsten and Rafael F. Miranda and Randa Kasmieh and Anna M. Krichevsky and Ralph Weissleder and Khalid Shah}, year={2007} }