Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113; Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113; Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
BMB Rep. 2022 Oct;55(10):506-511. doi: 10.5483/BMBRep.2022.55.10.037.
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. [BMB Reports 2022; 55(10): 506-511].
晚期肝细胞癌（HCC）是最难攻克的癌症之一，因此需要更好的治疗策略。在已用于临床的不同癌症药物中，索拉非尼被认为是晚期 HCC 的标准一线药物。在这里，为了鉴定一种与索拉非尼在 HCC 中具有协同作用的化学化合物，我们筛选了一个有针对性的化学文库，发现针对 MYST 家族的组蛋白乙酰转移酶抑制剂 MG149 与索拉非尼对 HCC 细胞具有最强的协同抗癌作用。索拉非尼和 MG149 的联合用药通过诱导细胞凋亡导致 HCC 细胞的协同抗增殖作用。我们揭示，索拉非尼和 MG149 的联合处理加剧内质网（ER）应激，以促进 HCC 细胞死亡而不是适应性细胞存活。此外，索拉非尼和 MG149 的联合治疗显著增加了未折叠蛋白和活性氧的细胞内水平，从而上调了 ER 应激。总的来说，这些结果表明，MG149 有可能通过上调细胞毒性 ER 应激来提高索拉非尼在晚期 HCC 中的疗效。[BMB 报告 2022；55(10)：506-511]。
