https://scholars.lib.ntu.edu.tw/handle/123456789/485690
Title: | Radiosensitizing effect of a phenylbutyrate-derived histone deacetylase inhibitor in hepatocellular carcinoma | Authors: | YEN-SHEN LU Chou C.-H. KAI-YUAN TZEN Gao M. ANN-LII CHENG Kulp S.K. CHIA-HSIEN CHENG |
Issue Date: | 2012 | Journal Volume: | 83 | Journal Issue: | 2 | Start page/Pages: | e181-e189 | Source: | International Journal of Radiation Oncology Biology Physics | Abstract: | Purpose: Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect associates with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC. Methods and Materials: Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response. Results: AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52% and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis. Conclusion: AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC. ? 2012 Elsevier Inc. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84862779596&doi=10.1016%2fj.ijrobp.2011.12.022&partnerID=40&md5=88033e6be91dedf85149cd50c07ac9f6 https://scholars.lib.ntu.edu.tw/handle/123456789/485690 |
ISSN: | 0360-3016 | DOI: | 10.1016/j.ijrobp.2011.12.022 | SDG/Keyword: | Cell cycle; Cell lines; Combined treatment; Conventional treatments; DNA repair; Hepatocellular carcinoma; Histone deacetylase inhibitor; Histone deacetylases; In-vitro; In-vivo; Multi-modal; Orthotopic; Pre-Treatment; Protein expressions; Radiation-induced; Radiosensitizers; Regulatory protein; Sublethal effects; Telomere maintenance; Therapeutic values; Tumor control; Tumor growth; Tumor suppression; Western blots; Biological materials; Cell culture; Cell death; Flow cytometry; Repair; Tumors; Radiotherapy; ar 42; histone deacetylase inhibitor; Ku antigen; radiosensitizing agent; unclassified drug; animal experiment; animal model; animal tissue; article; cancer radiotherapy; cell cycle; cell death; controlled study; DNA repair; flow cytometry; human; human cell; in vitro study; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; radiosensitivity; SCID mouse; tumor xenograft; Western blotting; Acetylation; Animals; Antigens, Nuclear; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Cobalt Radioisotopes; Combined Modality Therapy; DNA Repair; DNA, Neoplasm; DNA-Binding Proteins; Histone Deacetylase Inhibitors; Humans; Liver Neoplasms; Male; Mice; Mice, SCID; Molecular Targeted Therapy; Phenylbutyrates; Radiation-Sensitizing Agents; Radiotherapy Dosage; Random Allocation; Transplantation, Heterologous |
Appears in Collections: | 腫瘤醫學研究所 |
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