Sorafenib combined with dasatinib therapy inhibits cell viability, migration, and angiogenesis synergistically in hepatocellular carcinoma.

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.

• Authors: Chiung-Chi Cheng, Wei-Ting Chao, Jing-Hao Shih, Yih-Shyong Lai, Yung-Hsiang Hsu, Yi-Hsiang Liu
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 88 Issue 1 Pg. 143-153 (07 2021) ISSN: 1432-0843 [Electronic] Germany
• PMID: 33860837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor A
• Sorafenib
• Dasatinib

Topics

• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dasatinib (pharmacology)
• Hep G2 Cells
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism, pathology)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Signal Transduction (drug effects)
• Sorafenib (pharmacology)
• Vascular Endothelial Growth Factor A (metabolism)