Gemcitabine Sensitivity Evaluation in Pancreatic Ductal Adenocarcinoma Following Inhibition of ABCG2 and Wnt/p-Catenin Pathway

摘要

Purpose: Pancreatic cancer is one of the most lethal malignancies worldwide. Gemcitabine based therapy is currently the first-line treatment and usually fails to treat the patients with advanced pancreatic ductal adenocarcinoma (PDA) because of rapid acquisition of resistance to chemotherapy. Thus, identification of agents that re-sensitize gemcitabine-resistance pancreatic cancer cells to gemcitabine and exploring more about molecular mechanisms of gemcitabine resistance are essential to develop new therapeutic approaches for pancreatic cancer. Methods: In the present study, we report that FTC (an ABCG2 inhibitor) and IWR-1 endo (a Wnt/p-catenin signaling inhibitor) combination re-sensitize resistant AsPC-1 cells to gemcitabine as shown by MTT and western blot analysis. Main findings: IWR-1 and FTC co-incubation with different concentrations of gemcitabine (0.02, 0.04, 0.08, 0.16, 0.32, 0.64, 1.28, 2.56 umol) for 72 hours showed significant cell death effects, in which gemcitabine IC50 after IWR-1 endo or FTC added on AsPC-1GR (gemcitabine-resistance) cells were 1.35 and 1.58 (umol), respectively, while cell's viability remarkably reduced following co-treatment of IWR-1endo plus FTC with gemcitabine (gemcitabine IC50=0.1 umol) (p<0. 05).