Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

International Journal of Molecular Sciences
Subbroto Kumar SahaSsang-Goo Cho

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...Continue Reading

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Citations

Jun 2, 2018·Current Medicinal Chemistry·Faria SultanaAhmed Kamal
May 12, 2018·International Journal of Molecular Sciences·Subbroto Kumar SahaSsang-Goo Cho
Sep 4, 2020·Journal of Gastrointestinal Cancer·Bondada Venkata Mani Anirudh, Devaraj Ezhilarasan
May 3, 2019·Oncology Reviews·Mohamed AbdelaleemAlaa Refaat
Dec 11, 2020·BioMed Research International·Mohamed H YousefAnwar Abdelnaser
Apr 4, 2021·Journal of Personalized Medicine·Nikolaos GarmpisDimitrios Dimitroulis
Oct 2, 2021·Therapeutic Delivery·Jagadish NateshMuniasamy Neerathilingam

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Methods Mentioned

BETA
histone acetylation
glycosylation
PCR
Assay
fluorescence inverted microscopy
protein
electrophoresis

Software Mentioned

ImageJ
GraphPad InStat

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