Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalizationand Shows Synergistic Cytotoxic Effects in Hepatocellular CarcinomaCells

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/486832.do
DOI
10.3390/ijms18051048
Title
Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalizationand Shows Synergistic Cytotoxic Effects in Hepatocellular CarcinomaCells
Description
This work was supported by a grant from the National Research Foundation(NRF) funded by the Korean government (2013M3A9D3045880 and2015R1A5A1009701).
abstract
Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono-and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.
provenance
Made available in Cube on 2018-09-28T16:18:07Z (GMT). No. of bitstreams: 0
language
English
author
Saha, Subbroto Kumar
Yin, Yingfu
Kim, Kyeongseok
Yang, Gwang-Mo
Dayem, Ahmed Abdal
Choi, Hye Yeon
Cho, Ssang-Goo
orcid
Saha, Subbroto Kumar/0000-0003-1325-3499; Cho,
Ssang-Goo/0000-0002-0968-7932
accessioned
2018-09-28T16:18:07Z
available
2018-09-28T16:18:07Z
issued
2017
citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES(18): 5
issn
1422-0067
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/486832.do
Funder
과학기술정보통신부
Funding Program
집단연구지원
Project ID
1711048499
Jurisdiction
Rep.of Korea
Project Name
Humanized Pig Research Center
rights
openAccess
subject
valproic acid
doxorubicin
reactive oxygen species
autophagy
celldeath
caveolae endocytosis pathway
type
article


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