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Synergistic effect of targeting the epidermal growth factor receptor and hyaluronan synthesis in oesophageal squamous cell carcinoma cells
Author(s) -
Kretschmer I,
Freudenberger T,
Twarock S,
Fischer J W
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13240
Subject(s) - erlotinib , gefitinib , cancer research , epidermal growth factor receptor , cell growth , cancer , cell culture , erlotinib hydrochloride , egfr inhibitors , cell cycle , squamous carcinoma , cell , medicine , pharmacology , biology , carcinoma , biochemistry , genetics
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 ERK 1/2 phosphorylation. Conclusions and Implications The combination of 4‐ MU and erlotinib showed promising anti‐cancer efficacies in the ESCC cell lines.