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

Abstract 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.