Chiung-Chi Cheng1,2, Wei-Ting Chao3, Jing-Hao Shih3, Yih-Shyong Lai1, Yung-Hsiang Hsu4, Yi-Hsiang Liu5,6. 1. Department of Pathology, Chang Bing Show-Chwan Memorial Hospital, 6, Lugong Road, Lukang Zhen, Changhua County, 505, Taiwan. 2. Center for General Education, Providence University, 200, Section 7, Taiwan Boulevard, Shalu District, Taichung City, 433, Taiwan. 3. Department of Life Science, Tunghai University, 1727, Section 4, Taiwan Boulevard, Xitun District, Taichung City, 407, Taiwan. 4. Department of Pathology, Tzu Chi University, 701, Section 3, Jhongyang Road, Hualien, 97004, Taiwan. 5. Department of Pathology, Chang Bing Show-Chwan Memorial Hospital, 6, Lugong Road, Lukang Zhen, Changhua County, 505, Taiwan. ysliu53@gmail.com. 6. Department of Pathology, Tzu Chi University, 701, Section 3, Jhongyang Road, Hualien, 97004, Taiwan. ysliu53@gmail.com.
Abstract
PURPOSE: Sorafenib is a multikinase inhibitor used for treatment of advanced hepatocellular carcinoma. Sorafenib resistance may be related to Src-induced cell migration and angiogenesis, which are regulated by cancer stem cell activation and release of vascular endothelial growth factor. Dasatinib is a Src inhibitor that inhibits Src phosphorylation and suppresses Src-associated cell migration and angiogenesis. This study investigated whether combined treatment with dasatinib can overcome sorafenib resistance. METHODS: Hepatoma cell lines were used for sorafenib and/or dasatinib treatment. Cell viability, cell migration, molecular expressions, and release of vascular endothelial growth factor by hepatoma cells were evaluated. Hepatoma cell culture medium was applied on human umbilical vein endothelial cells to monitor angiogenesis promoted by the hepatoma cells. RESULTS: Sorafenib and dasatinib combined therapy suppressed cell viability of hepatoma cells synergistically. Dasatinib suppressed sorafenib-induced cell migration via inhibiting sorafenib-induced Src/FAK phosphorylation, cell-to-cell contact and cancer stem cell activation. Culture medium from Chang liver and PLC/PRF/5 cells suppressed angiogenesis of human umbilical vein endothelial cells with any treatment, whereas sorafenib-treated medium of HepG2 cells induced angiogenesis. This sorafenib-induced angiogenesis was then suppressed by dasatinib. Vascular endothelial growth factor released from hepatoma cells was also inhibited by combined treatment. CONCLUSION: Src/FAK phosphorylation and cancer stem cell activation inducing cell migration and angiogenesis may be the key factors of sorafenib resistance. Sorafenib and dasatinib combined treatment suppresses cell migration and angiogenesis by inhibiting the Src/FAK phosphorylation, cell-to-cell contact, cancer stem cell activation, and release of vascular endothelial growth factor.
PURPOSE:Sorafenib is a multikinase inhibitor used for treatment of advanced hepatocellular carcinoma. Sorafenib resistance may be related to Src-induced cell migration and angiogenesis, which are regulated by cancer stem cell activation and release of vascular endothelial growth factor. Dasatinib is a Src inhibitor that inhibits Src phosphorylation and suppresses Src-associated cell migration and angiogenesis. This study investigated whether combined treatment with dasatinib can overcome sorafenib resistance. METHODS:Hepatoma cell lines were used for sorafenib and/or dasatinib treatment. Cell viability, cell migration, molecular expressions, and release of vascular endothelial growth factor by hepatoma cells were evaluated. Hepatoma cell culture medium was applied on human umbilical vein endothelial cells to monitor angiogenesis promoted by the hepatoma cells. RESULTS:Sorafenib and dasatinib combined therapy suppressed cell viability of hepatoma cells synergistically. Dasatinib suppressed sorafenib-induced cell migration via inhibiting sorafenib-induced Src/FAK phosphorylation, cell-to-cell contact and cancer stem cell activation. Culture medium from Chang liver and PLC/PRF/5 cells suppressed angiogenesis of human umbilical vein endothelial cells with any treatment, whereas sorafenib-treated medium of HepG2 cells induced angiogenesis. This sorafenib-induced angiogenesis was then suppressed by dasatinib. Vascular endothelial growth factor released from hepatoma cells was also inhibited by combined treatment. CONCLUSION:Src/FAK phosphorylation and cancer stem cell activation inducing cell migration and angiogenesis may be the key factors of sorafenib resistance. Sorafenib and dasatinib combined treatment suppresses cell migration and angiogenesis by inhibiting the Src/FAK phosphorylation, cell-to-cell contact, cancer stem cell activation, and release of vascular endothelial growth factor.
Authors: Jordi Bruix; Jean-Luc Raoul; Morris Sherman; Vincenzo Mazzaferro; Luigi Bolondi; Antonio Craxi; Peter R Galle; Armando Santoro; Michel Beaugrand; Angelo Sangiovanni; Camillo Porta; Guido Gerken; Jorge A Marrero; Andrea Nadel; Michael Shan; Marius Moscovici; Dimitris Voliotis; Josep M Llovet Journal: J Hepatol Date: 2012-06-19 Impact factor: 25.083
Authors: Hannah van Malenstein; Jeroen Dekervel; Chris Verslype; Eric Van Cutsem; Petra Windmolders; Frederik Nevens; Jos van Pelt Journal: Cancer Lett Date: 2012-10-27 Impact factor: 8.679