Highly efficient eradication of intracranial glioblastoma using Eg5 siRNA combined with HVJ envelope.
Hemagglutinating virus of Japan envelope (HVJ-E) vector with inactivated replication-defective Sendai virus was originally developed as a versatile drug delivery system. Recently, we have shown the direct tumor-killing activity of HVJ-E itself without therapeutic molecules in prostate cancer cells. Although human glioblastoma cells were also sensitive to HVJ-E treatment, complete eradication was not achieved using HVJ-E alone. Here, to develop more effective therapeutic strategy of glioblastoma, we enhanced the anti-tumor activity by incorporating Short interfering RNA (siRNA) of mitotic motor protein Eg5 into HVJ-E. Treatment with HVJ-E-containing Eg5 siRNA induced monopolar spindle formation and resulted in cell-cycle arrest and apoptosis. When HVJ-E-containing Eg5 siRNA was directly injected into an intradermal tumor xenograft, all mice became tumor-free. Similar results were observed in the intracranial tumor xenografts. The survival time of treated mice was significantly prolonged when HVJ-E was used. Histological examination showed that tumors remained in the brain after treatment with HVJ-E-containing negative control siRNA, but no tumors were detected after treatment with HVJ-E-containing Eg5 siRNA. This remarkable anti-tumor response was likely due to a synergistic effect of Eg5 siRNA and HVJ-E. Thus, this combination shows promise as an attractive novel therapy for glioblastoma.
Matsuda
M
M
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Yamamoto
T
T
Matsumura
A
A
Kaneda
Y
Y
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000628:therapy*; D016547:Kinesins / Q000235:genetics*; D008297:Male; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D034741:RNA, Small Interfering; D029082:Sendai virus / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D014759:Viral Envelope Proteins; C521052:Kif11 protein, mouse; D016547:Kinesins