BMB Reports 2022; 55(10): 506-511  https://doi.org/10.5483/BMBRep.2022.55.10.037
Synergistic antitumor activity of sorafenib and MG149 in hepatocellular carcinoma cells
Byul Moon1,2, Mijin Park1,2, Seung-Hyun Cho1,3,†, Kang Mo Kim4, Haeng Ran Seo5, Jeong-Hoon Kim1,3,* & Jung-Ae Kim1,2,*
1Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113, 2Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, 3Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, 4Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, 5Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
Correspondence to: Jeong-Hoon Kim, Tel: +82-42-860-4264; Fax: +82-42-860-4598; E-mail: jhoonkim@kribb.re.kr; Jung-Ae Kim, Tel: +82-42-879-8129; Fax: +82-42-879-8119; E-mail: jungaekim@kribb.re.kr
†Current address: Uppthera R&D Center, Incheon 21988, Korea
Received: February 23, 2022; Revised: April 11, 2022; Accepted: June 9, 2022; Published online: October 31, 2022.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress.
Keywords: Cell death, ER stress, Hepatocellular carcinoma, MG149, Sorafenib

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