Radiosensitization Effect of STI-571 on Pancreatic Cancer Cells In Vitro

Purpose To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro. Methods and Materials Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor β (PDGFRβ) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4',6-diamidino-2-phenylindole were conducted. Results Dramatic phosphorylated ( p )-c-Kit and p -PDGFRβ attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p -c-Kit and p -PDGFRβ by STI-571, particularly to those of p -c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRβ, p -PLCγ was more closely related to radiosensitivity compared with p -Akt1 or p -extracellular signal-regulated kinase 1. Conclusion STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p -c-Kit or p -PDGFRβ, and K-ras mutation status. Among them, p -c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p -PDGFRβ or K-ras mutation status.