Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

Kuroda, Shigetoshi; Fujiwara, Toshiya; Shirakawa, Yasuhiro; Yamasaki, Yasumoto; Yano, Shuya; Uno, Futoshi; Tazawa, Hiroshi; Hashimoto, Yuichi; Watanabe, Yuichi; Noma, Kazuhiro; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi

doi:10.1158/0008-5472.can-10-2333

Cited by 69 publications

(56 citation statements)

References 39 publications

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“…During the infection with the telomerase-driven oncolytic adenovirus OBP301, the degradation of MRN complex was accompanied by greatly reduced levels of ATM activation (Kuroda et al 2010). It is possible that dl922-947 infection is not able to fully suppress the early events in DNA damage signaling, as MRN complex degradation may not in itself be sufficient to preclude/ reduce ATM and ATR kinase activation, as previously reported (Nichols et al 2009).…”

Section: Discussionmentioning

confidence: 64%

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Ionizing radiation enhances dl922–947-mediated cell death of anaplastic thyroid carcinoma cells

Abagnale¹,

Libertini²,

Volpe³

et al. 2013

Endocrine-Related Cancer

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dl922-947 is an oncolytic adenovirus potentially suitable for the treatment of aggressive localized tumors, such as anaplastic thyroid carcinoma (ATC). In this study, we have analyzed the effects of dl922-947 in combination with ionizing radiations, testing different schedules of administration and observing synergistic effects only when ATC cells were irradiated 24 h prior to viral infection. Cells undergoing combined treatment exhibited a marked increase in cell death and viral replication, suggesting that irradiation blocks cells in a more permissive state for viral life cycle. We also show that dl922-947 triggers a DNA damage response, characterized by mobilization of the MRN complex (composed by Mre11-Rad50-Nbs1), accumulation of gH2AX, and activation of the checkpoint kinases ataxia telangiectasia mutated (ATM) and Chk1. Based on these observations, we speculate that the DNA damage response acts as a cellular protective mechanism to hinder viral infection and replication. To confirm this hypothesis, we demonstrate that the ATM inhibitor KU55933 increased the oncolytic activity of dl922-947 and its replication. Finally, we validate the potential therapeutic use of this approach by showing in vivo that the combined treatment slows tumor xenograft growth more potently than either irradiation or infection alone.

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Section: Discussionmentioning

confidence: 64%

“…In a study using a telomerase-specific replication selective adenovirus (OBP-301), viral infection was shown to result in radiosensitivity in A459 small-cell lung cancer cells (Kuroda et al 2010). In the same study, a dose-dependent increase in adenoviral uptake and coxsackie adenovirus receptor expression was also observed.…”

Section: Discussionmentioning

confidence: 99%

Ionizing radiation enhances dl922–947-mediated cell death of anaplastic thyroid carcinoma cells

Abagnale¹,

Libertini²,

Volpe³

et al. 2013

Endocrine-Related Cancer

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“…27 We previously reported that OBP-301 enhances radiosensitization in human cancer cells by inhibition of the DNA repair machinery. 28 Based on these findings, combination therapy with OBP-301, VPA and radiation is an exceedingly promising antitumor therapy.…”

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confidence: 99%

Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells

et al. 2012

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Replication-selective oncolytic viruses are being developed for human cancer therapy. We previously developed an attenuated adenovirus Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site. OBP-301 can replicate in, and causes selective lysis of, human cancer cells. Valproic acid (VPA), which is an effective antiepileptic drug, is known to inhibit the histone deacetylase activities. We determined whether the antitumor effect of OBP-301 could be enhanced by VPA in human lung cancer cells. In an in vitro cell viability assay, OBP-301 infection killed four human lung cancer cell lines, H1299, H1299-R5 (a subline of H1299 with a low level of the coxsackievirus and adenovirus receptor (CAR) expression), H460, and A549, more efficiently in the presence of VPA than in its absence. VPA treatment increased CAR expression in all the four lung cancer cells. Consistent with their CAR upregulation, the infection efficiency of adenoviruses in the presence of VPA was significantly higher than that in its absence. The molecular mechanism of this combined effect could be explained by an increase in adenovirus infectivity via VPA-mediated upregulation of CAR. These results suggest that treatment with OBP-301 in combination with VPA is a promising strategy for human lung cancer.

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“…The MRN complex is a conserved protein complex that plays a key role in the response to DNA damage (19). Kuroda1 et al (20) demonstrated that degradation of MRN complex results in the inability to repair DNA double-strand breaks (DSB) and leads to radiosensitization, which indicates that RAD50 plays a key role in radioresistance.…”

Section: A B C D E F Discussionmentioning

confidence: 99%

Alteration of DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells

et al. 2015

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Abstract. The present study aimed to investigate the alteration of the DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells (GSLCs), and also aimed to explore potential targets for overcoming glioblastoma radioresistance. Serum-free medium was used to isolate and culture GSLCs. Cell growth was detected using a cell counting kit-8 assay and cell sorting analysis was performed by flow cytometry. X-ray irradiation was produced by a Siemens-Primus linear accelerator. Reverse transcription-quantitative polymerase chain reaction (qPCR) was performed to investigate target genes. SPSS 15.0 was used for all statistical analyses. Human glioblastoma U251 and U87 cells were cultured in serum-free medium supplemented with epidermal growth factor and fibroblast growth factor 2, which constitutes tumor sphere medium, and demonstrated sphere formation, with significantly increased the proportion of CD133 + and Nestin + cells, which are referred to as GSLCs. The present data revealed that treatment with 10 Gy X-ray radiation alters the expression profile of DNA damage-associated genes in GSLCs. The expression levels of 12 genes demonstrated a ≥2-fold increase in the irradiated U87 GSLCs compared with the untreated U87 GSLCs. Three genes, consisting of XPA, RAD50 and PPP1R15A, were selected from the 12 genes by gene functional searching and qPCR confirmatory studies, as these genes were considered to be potential targets for overcoming radioresistance. The expression of XPA, RAD50 and PPP1R15A is significantly increased in U87 and U251 radiation resistant GSLCs, indicating three potential targets for overcoming the radioresistance of GSLCs.

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Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

Cited by 69 publications

References 39 publications

Ionizing radiation enhances dl922–947-mediated cell death of anaplastic thyroid carcinoma cells

Ionizing radiation enhances dl922–947-mediated cell death of anaplastic thyroid carcinoma cells

Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells

Alteration of DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells

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