Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to ProtonTherapy by Suppressing NRF2 Activation

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/486835.do
DOI
10.1038/s41598-017-15165-3
Title
Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to ProtonTherapy by Suppressing NRF2 Activation
Description
We would like to thank Professor Youngyui Han and the medical physicistsin Samsung Medical Center for their helpful discussion and assistancewith irradiation experiments. This research was supported by SamsungMedical Center grants (GF01130081 and SMX1170051), the Basic ScienceResearch Program through the National Research Foundation of Koreafunded by the Ministry of Education (NRF-2015R1D1A1A01060945) and theMarine Biotechnology Program funded by Ministry of Oceans and Fisheries,Korea (20150220).
abstract
Although efficacy of combined histone deacetylase (HDAC) inhibitors and conventional photon radiotherapy is being tested in clinical trials, their combined effect with proton beam radiotherapy has yet to be determined. Here, we compared combined effect of valproic acid (VPA), a class I and II HDAC inhibitor and antiepileptic drug with proton and photon irradiation in hepatocellular carcinoma (HCC) cells in vitro and in vivo. We found that VPA sensitized more Hep3B cells to proton than to photon irradiation. VPA prolonged proton-induced DNA damage and augmented proton-induced apoptosis. In addition, VPA further increased proton-induced production of intracellular reactive oxygen species and suppressed expression of nuclear factor erythroid-2-related factor 2 (NRF2), a key transcription factor regulating antioxidant response. Downregulation of NRF2 by siRNA transfection increased proton-induced apoptotic cell death, supporting NRF2 as a target of VPA in radiosensitization. In Hep3B tumor xenograft models, VPA significantly enhanced proton-induced tumor growth delay with increased apoptosis and decreased NRF2 expression in vivo. Collectively, our study highlights a proton radiosensitizing effect of VPA in HCC cells. As NRF2 is an emerging prognostic marker contributing to radioresistance in HCC, targeting NRF2 pathway may impact clinical outcome of proton beam radiotherapy.
provenance
Made available in Cube on 2018-09-28T16:18:11Z (GMT). No. of bitstreams: 0
language
English
author
Il Yu, Jeong
Choi, Changhoon
Shin, Sung-Won
Son, Arang
Lee, Ga-Haeng
Kim, Shin-Yeong
Park, Hee Chul
accessioned
2018-09-28T16:18:11Z
available
2018-09-28T16:18:11Z
issued
2017
citation
SCIENTIFIC REPORTS(7)
issn
2045-2322
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/486835.do
Funder
해양수산부
Funding Program
해양수산생명공학기술개발
Project ID
1525006555
Jurisdiction
Rep.of Korea
Project Name
(핵심과제1)해양 융복합 바이오닉스 진단기기 개발
rights
openAccess
type
article


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