TY - JOUR
T1 - Enhanced oncolytic activities of the telomerase-specific replication-competent adenovirus expressing short-hairpin RNA against dicer
AU - Machitani, Mitsuhiro
AU - Sakurai, Fuminori
AU - Wakabayashi, Keisaku
AU - Tachibana, Masashi
AU - Fujiwara, Toshiyoshi
AU - Mizuguchi, Hiroyuki
N1 - Funding Information:
We thank Sayuri Okamoto and Eri Hosoyamada (Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan) for their help. This work was supported by grants-in-aid for Scientific Research (A) to H. Mizuguchi, (B) to F. Sakurai, and for Young Scientists (A) to F. Sakurai from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan and by grants from the Mochida Memorial Foundation for Medical and Pharmaceutical Research to H. Mizuguchi. M. Machitani and K. Wakabayashi are Research Fellows of the Japan Society for the Promotion of Science.
Publisher Copyright:
©2016 AACR.
PY - 2017/1
Y1 - 2017/1
N2 - Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing shorthairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity.
AB - Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing shorthairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity.
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U2 - 10.1158/1535-7163.MCT-16-0383
DO - 10.1158/1535-7163.MCT-16-0383
M3 - Article
C2 - 27760834
AN - SCOPUS:85010041639
VL - 16
SP - 251
EP - 259
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 1
ER -