MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.
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.
Corsten
Maarten F
MF
Center for Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Miranda
Rafael
R
Kasmieh
Randa
R
Krichevsky
Anna M
AM
Weissleder
Ralph
R
Shah
Khalid
K
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics*; D013234:Stem Cells / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014162:Transfection
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D053221:TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases