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

doi:10.1016/j.omto.2017.10.003

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

Mol Ther Oncolytics. 2017 Oct 26:7:76-85. doi: 10.1016/j.omto.2017.10.003. eCollection 2017 Dec 15.

Authors

Mitsuhiro Machitani^{1

2}, Fuminori Sakurai^{1

3}, Keisaku Wakabayashi¹, Kosuke Nakatani¹, Masashi Tachibana^{1

4}, Nobuyuki Kato⁵, Toshiyoshi Fujiwara⁶, Hiroyuki Mizuguchi^{1

4

7

8

9}

Affiliations

¹ Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
³ Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Unit, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁴ Global Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁵ Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
⁶ Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
⁷ Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito, Asagi, Ibaraki, Osaka 567-0085, Japan.
⁸ iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁹ Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

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.

Keywords: NF-κB; hepatotoxicity; liver-specific promoter; oncolytic adenovirus.