Transforming Growth Factor Beta Receptor I Inhibitor Sensitizes Drug-resistant Pancreatic Cancer Cells to Gemcitabine

Background: Resistance to gemcitabine is a major obstacle in the treatment of advanced pancreatic cancer. Previous exploration of protein kinase inhibitors demonstrated that blocking transforming growth factor-β (TGFβ) signal enhances the efficacy of gemcitabine in pancreatic cancer cells. Materials and Methods: We analyzed the cell viability after combinational treatment of TGFβ receptor I (TβRI) inhibitors, SB431542 and SB525334 with gemcitabine in pancreatic cancer cells. In addition, apoptotic cell death and cell migration were measured. Results: Combination with TβRI inhibitors significantly augmented the cytotoxicity of gemcitabine in both parental and gemcitabine resistant pancreatic cancer cells. SB525334 significantly increased apoptotic cell death in gemcitabine-resistant cells. Treatment of SB525334 also affected the AKT signalling pathway, which plays a crucial role in gemcitabine resistance. Migration assay also revealed that blocking TβRI reduces cell migration. Conclusion: Chemotherapeutic approaches using SB525334 might enhance the treatment benefit of the gemcitabine-containing regimens in the treatment of pancreatic cancer patients.