AZD5153 enhances the chemo-sensitivity of gemcitabine on pancreatic cancer cells in vitro and in vivo

Background : Pancreatic cancer is a malignant cancer with apoor prognosis. Gemcitabine (GEM), the first-line treatment drug, shows limited efficacy because of the notorious drug resistance of pancreatic cancer. Therefore, thedevelopment ofsensitive drugsfor pancreatic cancer is essential. AZD5153 is a novel bivalent BET bromodomain inhibitor with multiple antitumor effects on malignancy. Here, we aimed to investigate the effect of AZD5153 on the GEM sensitivity in human pancreatic cancer cells. Methods : Sulforhodamine B (SRB), clone formation assays were designed to characterize the cell viability and clone formation after treatment with AZD5153 and/or GEM. Flow cytometry and western blotting were used to identify the cell apoptosis. RNA-seq analysis, western blotting and qPCR were also conducted to confirm the signaling pathway involved in it. Results : As a result, AZD5153 presented a strong anti-proliferation activity, exerted the synergistic effects in combined with GEM both in vitro and in vivo . AZD5153 combined with GEM induced cell apoptosis. Further investigations revealed that the combination of AZD5153 and GEM decreased the phosphorylation of ERK/mTOR signaling proteins. Besides, the expression of BRD4 is unchanged, while the MUC2 expression is remarkable decreased after combination treatment. Conclusion : In conclusion, these results suggested that AZD5153 might be an excellent GEM sensitizer in pancreatic cancer.