Sorafenib and DE605, a novel c-Met inhibitor, synergistically suppress hepatocellular carcinoma
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Xiufeng Jiang1,2, Kang Feng2, Ye Zhang1, Zengyao Li2, Fan Zhou2, Huiqiang Dou1, Tong Wang1,2
1 Department of General Surgery, Wuxi People’s Hospital, Wuxi, China
2 Nanjing Medical University, Nanjing, China
* These authors have contributed equally to this work
Tong Wang, email:
Keywords: c-Met inhibitor, sorafenib, combination, hepatocellular carcinoma
Received: January 15, 2015 Accepted: February 26, 2015 Published: March 26, 2015
Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.
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