Valproic acid overcomes sorafenib resistance by reducing the migration of Jagged2-mediated Notch1 signaling pathway in hepatocellular carcinoma cells
- Int J Biochem Cell Biol. 2020 Sep;126:105820. doi: 10.1016/j.biocel.2020.105820.
- 1. Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
- 2. Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China. Electronic address: [email protected].
Sorafenib resistance is a classic problem related to the treatment of advanced hepatocellular carcinoma (HCC). There is a recognized need to explore new drug resistance mechanisms and develop novel strategies to overcome the acquired resistance to sorafenib. Although one study has showed that the anti-epileptic drug valproic acid (VPA) could sensitize transforming growth factor-β (TGF-β)-induced sorafenib-resistant HCC cells, it is unclear whether VPA could reverse resistance to long-term clinical treatment with sorafenib. In this study, we successfully established sorafenib-resistant HCC cells by long-term sorafenib exposure. Compared with sensitive HCC cells, the proliferation, anti-apoptotic capability and migration of the sorafenib-resistant cells were enhanced. In addition, we found that VPA combined with sorafenib could overcome drug resistance by downregulating Jagged2-mediated Notch1 signaling pathway and epithelial-mesenchymal transition (EMT)-related proteins. Furthermore, the combination of VPA and sorafenib could obviously increase the sensitivity of drug-resistant cells in vitro and synergistically suppress tumor growth in vivo. These results provided a new insight that the use of VPA in combination with sorafenib was an effective method for clinically solving the problem of sorafenib resistance by modulating the Jagged2-mediated Notch1 signaling pathway and reversing the EMT phenotype.