Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells.

Abstract

BACKGROUND:

Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.

METHODS:

Growth inhibition was assessed by MTS assay. EGFR, Src and downstream proteins FAK, Akt, MAPK42/44, Stat3 expressions were measured by western blot. Cell adhesion, migration and invasion were performed with and without dasatinib treatment.

RESULTS:

The IC50 of 9 cell lines ranged from 0.7 μM ~ 14.2 μM. In general the growth inhibition by dasatinib was related to total Src (t-Src) and the ratio of activated Src (p-Src) to t-Src. There was good correlation of the sensitivity to dasatinib and the inhibition level of p-Src, p-FAK576/577 and p-Akt. No inhibition was found on Stat3 and MAPK42/44 in all cell lines. The inhibition of cell adhesion, migration and invasion were correlated with p-FAK inhibition.

CONCLUSION:

Dasatinib inhibits the proliferation, adhesion, migration and invasion of HCC cells in vitro via inhibiting of Src tyrosine kinase and affecting SFK/FAK and PI3K/PTEN/Akt, but not Ras/Raf/MEK/ERK and JAK/Stat pathways. T-Src and p-Src/t-Src may be useful biomarkers to select HCC patients for dasatinib treatment.

• Authors: Alex Y Chang, Miao Wang
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 267 (May 30 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23721490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Dasatinib

Topics

• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dasatinib
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology)
• Tumor Cells, Cultured