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

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 IC(50) 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

High-dimensional Schwarzschild black holes in scalar-tensor-vector gravity theory

We obtain a high-dimensional Schwarzschild black hole solution in the scalar-tensor-vector gravity (STVG), and then analyze the influence of parameter $\alpha$ associated with a deviation of the STVG theory from General Relativity on event horizons and Hawking temperature. We calculate the quasinormal mode frequencies of massless scalar field perturbations for the high-dimensional Schwarzschild STVG black hole by using the sixth-order WKB approximation method and the unstable null geodesic method in the eikonal limit. The results show that the increase of parameter $\alpha$ makes the scalar waves decay slowly, while the increase of the spacetime dimension makes the scalar waves decay fast. In addition, we study the influence of parameter $\alpha$ on the shadow radius of this high-dimensional Schwarzschild STVG black hole and find that the increase of parameter $\alpha$ makes the black hole shadow radius increase, but the increase of the spacetime dimension makes the black hole shadow radius decrease. Finally, we investigate the energy emission rate of the high-dimensional Schwarzschild STVG black hole, and find that the increase of parameter $\alpha$ makes the evaporation process slow, while the increase of the spacetime dimension makes the process fast.Comment: v1: 18 pages, 6 figures, 4 tables; v2: clarifications and references added; v3: 19 pages, final version to appear in European Physical Journal