Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Subbroto Kumar Saha
ORCID logo ,
Yingfu Yin
ORCID logo ,
Kyeongseok Kim
,
Gwang-Mo Yang
,
Ahmed Abdal Dayem
ORCID logo ,
Hye Yeon Choi
,
Ssang-goo Cho
* ORCID logo
Version 1 : Received: 31 March 2017 / Approved: 31 March 2017 / Online: 31 March 2017 (12:08:53 CEST)

A peer-reviewed article of this Preprint also exists.

Saha, S.K.; Yin, Y.; Kim, K.; Yang, G.-M.; Dayem, A.A.; Choi, H.Y.; Cho, S.-G. Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells. Int. J. Mol. Sci. 2017, 18, 1048. Saha, S.K.; Yin, Y.; Kim, K.; Yang, G.-M.; Dayem, A.A.; Choi, H.Y.; Cho, S.-G. Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells. Int. J. Mol. Sci. 2017, 18, 1048.

Abstract

We evaluated the mono- and combination-therapy effects of valproic acid (VPA) and doxorubicin (DOX) in hepatocellular carcinoma (HCC) and identified 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.

Keywords

valproic acid; doxorubicin; reactive oxygen species; autophagy; cell death; caveolae endocytosis pathway

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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