Journal Article

Adenovirus-mediated FIR demonstrated TP53-independent cell-killing effect and enhanced antitumor activity of carbon-ion beams

Hiwasa, T, Matsushita, K, Yamada, S, Matsubara, H, Nomura, F, Kano, M, Rahmutulla, B, Kubo, S, Shimada, H

2016

Overview

Combination therapy of carbon-ion beam with the far upstream element-binding protein (FBP)-interacting repressor, FIR, which interferes with DNA damage repair proteins, was proposed as an approach for esophageal cancer treatment with low side effects regardless of TP53 status. In vivo therapeutic antitumor efficacy of replication-defective adenovirus (E1 and E3 deleted adenovirus serotype 5) encoding human FIR cDNA (Ad-FIR) was demonstrated in the tumor xenograft model of human esophageal squamous cancer cells, TE-2. Bleomycin (BLM) is an anticancer agent that introduces DNA breaks. The authors reported that Ad-FIR involved in the BLM-induced DNA damage repair response and thus applicable for other DNA damaging agents. To examine the effect of Ad-FIR on DNA damage repair, BLM, X-ray and carbon-ion irradiation were used as DNA damaging agents. The biological effects of high linear energy transfer (LET) radiotherapy used with carbon-ion irradiation are more expansive than low-LET conventional radiotherapy, such as X-rays or γ rays. High LET radiotherapy is suitable for the local control of tumors because of its high relative biological effectiveness. Ad-FIR enhanced BLM-induced DNA damage indicated by γH2AX in vitro . BLM treatment increased endogenous nuclear FIR expression in TE-2 cells, and P27Kip1 expression was suppressed by TP53 siRNA and BLM treatment. Further, Ad-FIRΔexon2, a dominant-negative form of FIR that lacks exon2 transcriptional repression domain, decreased Ku86 expression. The combination of Ad-FIR and BLM in TP53 siRNA increased DNA damage. Additionally, Ad-FIR showed synergistic cell toxicity with X-ray in vitro and significantly increased the antitumor efficacy of carbon-ion irradiation in the xenograft mouse model of TE-2 cells ( P =0.03, Mann–Whitney’s U- test) and was synergistic with the sensitization enhancement ratio (SER) value of 1.15. Therefore, Ad-FIR increased the cell-killing activity of the carbon-ion beam that avoids late-phase severe adverse effects independently of the TP53 status in vitro . Our findings indicated the feasibility of the combination of Ad-FIR with DNA damaging agents for future esophageal cancer treatment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/44 / 42/89 / 631/61/51/201 / 631/67 / 631/67/1059 / 631/67/1504/1477 / 64/60 / 692/699 / Adenoviridae - genetics / Adenovirus / Adenoviruses / Analysis / Animals / Binding proteins / Biomedical and Life Sciences / Biomedicine / Bleomycin - pharmacology / Care and treatment / Cell Biology / Cell Line, Tumor / Combined Modality Therapy / Development and progression / Disease Models, Animal / DNA damage / DNA Damage - drug effects / DNA repair / DNA Repair - drug effects / Esophageal cancer / Esophageal Neoplasms - drug therapy / Female / Gene Expression / Gene Knockdown Techniques / Gene Therapy / Genetic aspects / Genetic Vectors / Health aspects / Heavy Ion Radiotherapy - methods / HeLa Cells / Human Genetics / Humans / Methods / Mice / Mice, Inbred BALB C / Nanotechnology / original-article / Patient outcomes / Proteins / Radiotherapy / Repressor Proteins - genetics / Repressor Proteins - metabolism / RNA Splicing Factors / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / X-Rays / Xenograft Model Antitumor Assays