Abstract
To test the hypothesis that chemoresistance in pancreatic cancer is mediated via extracellular signal-regulated protein kinase (ERK) 1/2 overactivity. The human pancreatic cancer cell lines BxPC3, PANC-1 and a stably gemcitabine-resistant subline, PANC1(GemRes), were treated with combinations of gemcitabine and the ERK1/2 inhibitor, U0126. Phosphorylated (p)ERK1/2 was examined by Western blotting; cell proliferation and apoptosis were quantified. A nude mouse xenograft model was established with each cell line, and the therapeutic efficacy of gemcitabine and U0126 alone or in combination was examined. Gemcitabine treatment visibly increased pERK1/2 levels in BxPC-3 and PANC-1 cells. PANC-1(GemRes) constitutively produced high levels of pERK1/2. U0126 treatment reversed the gemcitabine-associated increase in cell proliferation and reduction in apoptosis, in all three cell lines. Combination treatment with U0126 and gemcitabine inhibited tumour growth and promoted apoptosis in xenograft tumours derived from all three cell lines. ERK1/2 activity may protect pancreatic cancer cells from chemotherapy-induced apoptosis. The combined use of an ERK1/2 inhibitor (such as U0126) together with gemcitabine may result in synergistic therapeutic effects at tolerable gemcitabine doses.
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