Combination of FGFR4 inhibitor Blu9931 and 5-fluorouracil effects on the biological characteristics of colorectal cancer cells.

Abstract

The aim of this study was to explore the effects of single agent treatments and combination of Blu9931 and 5-fluorouracil (5-FU) on the biological characteristics of colorectal cancer cells and its mechanism. Blu9931 is the first selective small molecule inhibitor of the fibroblast growth factor receptor4 (FGFR4) and exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. The colorectal cancer cells HCT116 and SW620 with high expression of FGFR4 were selected for a series of functional tests including cell viability, cell proliferation, apoptosis and cell cycle detection. Western blotting was used to detect the expression of related molecules including signal pathway (STAT3), apoptosis (cleaved caspase‑3), cell cycle (cyclinD1 and P27kip1) and epithelial-mesenchymal transition (E-cadherin and vimentin) in HCT116 and SW620 cells used as single and combination treatments of 5‑FU and Blu9931. The cell viability gradually decreased when the concentration of 5‑FU and Blu9931 increased. Blu9931 can inhibit FGFR4 protein expression while 5‑FU cannot, as assessed by western blot analysis. The single agent treatment and combinations of 5‑FU and Blu9931 arrest cell cycle (P<0.05), increased p27kip1 expression and reduced cyclinD1 expression. The single agent treatment and combinations of 5‑FU and Blu9931 inhibited EMT. Furthermore, the combination of 5‑FU and Blu9931 has a synergistic effect in reducing colorectal cancer cell proliferation and preventing cell cycle. Taken together, this study provides the first evidence that Blu9931 functions as a FGFR4-selective inhibitor in colorectal cancer (CRC) cells, and Blu9931 may be a new targeted drug.