Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB

Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Kosuke Nakatani, Masashi Tachibana, Nobuyuki Kato, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

Research output: Contribution to journalArticle

Abstract

Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-κB (NF-κB) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα) expression cassette (TRAD-DNIκBα). Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

Original languageEnglish
Pages (from-to)76-85
Number of pages10
JournalMolecular Therapy - Oncolytics
Volume7
DOIs
Publication statusPublished - Dec 15 2017

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Adenoviridae
Gene Expression
Liver
Hepatocytes
Safety
Neoplasms
Telomerase
Intravenous Administration
Cell Line
Therapeutics

Keywords

  • hepatotoxicity
  • liver-specific promoter
  • NF-κB
  • oncolytic adenovirus

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB. / Machitani, Mitsuhiro; Sakurai, Fuminori; Wakabayashi, Keisaku; Nakatani, Kosuke; Tachibana, Masashi; Kato, Nobuyuki; Fujiwara, Toshiyoshi; Mizuguchi, Hiroyuki.

In: Molecular Therapy - Oncolytics, Vol. 7, 15.12.2017, p. 76-85.

Research output: Contribution to journalArticle

Machitani, Mitsuhiro ; Sakurai, Fuminori ; Wakabayashi, Keisaku ; Nakatani, Kosuke ; Tachibana, Masashi ; Kato, Nobuyuki ; Fujiwara, Toshiyoshi ; Mizuguchi, Hiroyuki. / Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB. In: Molecular Therapy - Oncolytics. 2017 ; Vol. 7. pp. 76-85.
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