Synergistic effect of targeting the epidermal growth factor receptor and hyaluronan synthesis in oesophageal squamous cell carcinoma cells.

BACKGROUND AND
PURPOSE: Worldwide, oesophageal cancer is the eighth most common cancer and has a very poor survival rate. In order to identify new tolerable treatment options for oesophageal squamous cell carcinoma (ESCC), erlotinib was tested with moderate efficacy in phase I and II studies. As 4-methylumbelliferone (4-MU), an hyaluronan (HA) synthesis inhibitor showed anti-cancer effects in vitro, and in ESCC xenograft tumours, we investigated whether the anti-cancer effects of erlotinib could be augmented by combining it with 4-MU. EXPERIMENTAL APPROACH: ESCC cell lines were treated with erlotinib or gefitinib (1 μmol·L-1 ) and 4-MU (300 μmol·L-1 ), and the cell count, cell cycle progression and migration were determined as compared to the single agents and the solvent-control. KEY
RESULTS: The combination of erlotinib and 4-MU synergistically inhibited the proliferation of ESCC cell lines. Furthermore, the migration speed of ESCC cell line KYSE-410 in gap closure assays was significantly reduced by the combination of erlotinib and 4-MU. Decreased ERK phosphorylation could explain the anti-proliferative and anti-migratory effects in the combined treatment group. Finally, the combination was additionally able to decrease the growth of multicellular tumour spheroids, a three-dimensional cell culture model that was associated with sustained inhibition of ERK1/2 phosphorylation. CONCLUSIONS AND IMPLICATIONS: The combination of 4-MU and erlotinib showed promising anti-cancer efficacies in the ESCC cell lines.