ARQ-197 enhances the antitumor effect of sorafenib in hepatocellular carcinoma cells via decelerating its intracellular clearance

Xudong Gao,1,2 Hebing Chen,1 Xin Huang,1 Hao Li,1 Zhen Liu,1 Xiaochen Bo1 1Beijing Institute of Radiation Medicine, Beijing 100850, People’s Republic of China; 2The 5th Medical Center of PLA General Hospital, Beijing 100039, People’s Republic of China Background: Hepatocellular carcinoma (HCC) is one of the heaviest malignant burdens in China. Molecular targeting agent, sorafenib, is the main therapeutic option for antitumor therapy of advanced HCC, but it is currently too expensive for the public and its therapeutic effect does not satisfy initial expectation. Therefore, it is important to develop more effective molecular targeted therapeutic strategies for advanced HCC. Materials and methods: The antitumor effects of sorafenib or ARQ-197, an antagonist of c-MET (tyrosine-protein kinase Met or hepatocyte growth factor receptor), were examined by MTT or in murine tumor model. The effect of ARQ-197 on epithelial–mesenchymal transition (EMT) or multidrug resistance (MDR) was examined by quantitative real-time PCR for the expression of related genes. The clearance of sorafenib in HCC cells was detected by liquid chromatography-mass spectrometry/mass spectrometry. Results: ARQ-197 treatment enhanced the sensitivity of HCC cells to sorafenib. Mechanistic studies indicated that ARQ-197 inhibited the expression of EMT- and MDR-related genes. Moreover, ARQ-197 treatment decelerated the clearance of sorafenib in cultured HCC cells and subcutaneous HCC tumors in nude mice. Conclusion: In the present work, our data suggested that ARQ-197 decelerated the clearance of sorafenib in HCC cells and enhanced the antitumor effect of sorafenib. Keywords: advanced hepatocellular carcinoma, molecular targeted agents, ARQ-197 and sorafenib, drug clearance, epithelial–mesenchymal transition, multidrug resistance