Antisense Oligonucleotide Inhibition of Tumor Necrosis Factor Receptor 1 Protects the Liver from Radiation-Induced Apoptosis

Huang, Xiqiang; Yang, Jiong; Dragovic, Aleksandar F.; Zhang, Hong; Lawrence, Theodore S.; Zhang, Ming

doi:10.1158/1078-0432.ccr-06-0360

Cited by 37 publications

(33 citation statements)

References 32 publications

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“…Similar to our previous findings in the liver (35), radiation caused an elevation of TNF-a in the lungs of BALB/c mice in a dosedependent manner. An increase in TNF-a of f68% (1,259 F 89 pg/mg) was observed as early as 3 hours after 15 Gy compared with the levels immediately after radiation (746 F 51 pg/mg) or in nonirradiated control mice (-RT; 754 F 45 pg/mg; Fig.…”

Section: Resultssupporting

confidence: 91%

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Inhibition of the Tumor Necrosis Factor-α Pathway Is Radioprotective for the Lung

Zhang

Qian

Xing

et al. 2008

Clinical Cancer Research

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Purpose: Radiation-induced lung toxicity limits the delivery of high-dose radiation to thoracic tumors. Here, we investigated the potential of inhibiting the tumor necrosis factor-a (TNF-a) pathway as a novel radioprotection strategy. Experimental Design: Mouse lungs were irradiated with various doses and assessed at varying times for TNF-a production. Lung toxicity was measured by apoptosis and pulmonary function testing. TNF receptor 1 (TNFR1) inhibition, achieved by genetic knockout or antisense oligonucleotide (ASO) silencing, was tested for selective lung protection in a mouse lung metastasis model of colon cancer. Results: Lung radiation induced local production ofTNF-a by macrophages in BALB/c mice 3 to 24 hours after radiation (15 Gy). A similar maximal induction was found 1week after the start of radiation when 15 Gy was divided into five daily fractions. Cell apoptosis in the lung, measured by terminal deoxyribonucleotide transferase^mediated nick-end labeling staining (mostly epithelial cells) and Western blot for caspase-3, was induced by radiation in a dose-and time-dependent manner. Specific ASO inhibited lungTNFR1expression and reduced radiation-induced apoptosis. Radiation decreased lung function in BALB/c and C57BL mice 4 to 8 weeks after completion of fractionated radiation (40 Gy). Inhibition of TNFR1 by genetic deficiency (C57BL mice) or therapeutic silencing with ASO (BALB/c mice) tended to preserve lung function without compromising lung tumor sensitivity to radiation. Conclusion: Radiation-induced lung TNF-a production correlates with early cell apoptosis and latent lung function damage. Inhibition of lung TNFR1 is selectively radioprotective for the lung without compromising tumor response.These findings support the development of a novel radioprotection strategy using inhibition of theTNF-a pathway.

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Section: Resultssupporting

confidence: 91%

“…Our previous study showed that radiation induces liver damage through TNF-a/TNFR1 activation and that inhibition of TNFR1 by ASO is radioprotective in liver (35). In this study, we examined the role of TNF-a in radiation-induced lung toxicity.…”

mentioning

confidence: 98%

Inhibition of the Tumor Necrosis Factor-α Pathway Is Radioprotective for the Lung

Zhang

Qian

Xing

et al. 2008

Clinical Cancer Research

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“…Our finding is corroborated by a recent study by Huang et al who showed that antisense oligonucleotides for TNF-α receptor could protect radiation-induced liver injury [16]. Because there were only 5 mice used per group, these results are considered preliminary and further investigations are needed in order to conclude that UTL-5g is a lung radioprotector.…”

Section: Tumor-response To Radiationsupporting

confidence: 87%

UTL-5g Lowers Levels of TGF-Î² and TNF-Î± Elevated by Lung Irradiation and Does Not Affect Tumor-response to Irradiation

Brown¹,

Valeriote²,

Chen³

et al. 2014

Am. J. Biomed. Sci.

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UTL-5g is a small-molecule TNF- inhibitor having chemoprotective and liver radioprotective effects. We investigated the effects of UTL-5g on lung irradiated mice and whether UTL-5g affects tumor responses to radiotherapy. C57BL/6 mice were individually treated with UTL-5g at 15, 30, and 60 mg/kg and amifostine (200 mg/kg) by i.p. injection 30 min prior to lung irradiation of 6 Gy (daily x 5). Two mice in the amifostine group died within 8 wks. At the first time point (8 wks), the plasma levels of TGF-β elevated by irradiation were significantly reduced by UTL-5g at 60 mg/kg (p<0.05). For the second time point (5 months), elevated levels of TNF-α in lung tissue from the irradiated group were suppressed by UTL-5g in a dose-dependent manner and was statistically significant at 60 mg/kg (p<0.05). Amifostine also showed a similar effect but at a much higher dose, 200 mg/kg (p <0.05). Incidentally, it was observed that UTL-5g delayed the radiation-induced hair-discoloration significantly ( >60 days after lung irradiation). The results indicate that UTL-5g may protect melanocytes against radiation-induced injury. Next, the effects of UTL-5g on tumor response were investigated in CD-1 nu/nu athymic nude mice bearing intramuscular A549 tumors (human non-small cell lung carcinoma) implanted in the right gastrocnemius muscle. Animals were treated with UTL-5g (30 mg/kg i.p.) 30 min prior to or after irradiation (5 Gy) daily for five days. The results showed that UTL-5g did not protect tumor from radiation damage. These observations suggest that UTL-5g may be lung radioprotective and thus, warranted further investigation.

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“…In a recent paper by Huang et al [37], the authors show that mice pre-treated with antisense oligonucleotides for TNFR1 when compared to control mice show less radiationinduced liver damage as measured by increment of transaminases and by the TUNEL method, which supports our thesis that TNF-released by KupVer cells and/or macrophages due to irradiation Wnally may lead to apoptosis of hepatocytes via the pathway described above. Huang et al [37] also demonstrated that pre-treatment of their mice with antisense oligonucleotides for FAS did not prevent radiationinduced liver apoptosis.…”

Section: Evect Of I B-antisense On Susceptibility Of Irradiated Hepatsupporting

confidence: 84%

“…Huang et al [37] also demonstrated that pre-treatment of their mice with antisense oligonucleotides for FAS did not prevent radiationinduced liver apoptosis. In our system however, using FASL (CD95L) in a similar approach as used for TNF-, apoptosis of hepatocytes could be observed (data not shown).…”

Section: Evect Of I B-antisense On Susceptibility Of Irradiated Hepatmentioning

confidence: 99%

Irradiation leads to sensitization of hepatocytes to TNF-α-mediated apoptosis by upregulation of IκB expression

Gürleyen

Christiansen

Tello

et al. 2008

Radiat Environ Biophys

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This study aimed to reveal the pathophysiological signalling responsible for radiation-induced sensitization of hepatocytes to TNF--mediated apoptosis. I B was upregulated in irradiated hepatocytes. Administration of I B antisense oligonucleotides prior to irradiation inhibited occurrence of apoptosis after TNF-administration. Caspases-8, -9 and -3 activities were increased in irradiated hepatocytes and downregulation of apoptosis by I B antisense oligonucleotides was mediated by suppression of caspases-9 and -3 activation but not of caspase-8 activation, suggesting that radiation-induced sensitization of hepatocytes to TNF--mediated apoptosis additionally requires changes upstream of caspase-8 activation. Herein, upregulation of FLIP may play a crucial role. Cleavage of bid, upregulation of bax, downregulation of bcl-2 and release of cytochrome c after TNF--administration depend on radiation-induced upregulation of I B, thus demonstrating an apoptosis permitting eVect of I B.

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Antisense Oligonucleotide Inhibition of Tumor Necrosis Factor Receptor 1 Protects the Liver from Radiation-Induced Apoptosis

Cited by 37 publications

References 32 publications

Inhibition of the Tumor Necrosis Factor-α Pathway Is Radioprotective for the Lung

Inhibition of the Tumor Necrosis Factor-α Pathway Is Radioprotective for the Lung

UTL-5g Lowers Levels of TGF-Î² and TNF-Î± Elevated by Lung Irradiation and Does Not Affect Tumor-response to Irradiation

Irradiation leads to sensitization of hepatocytes to TNF-α-mediated apoptosis by upregulation of IκB expression

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