Imatinib mesylate radiosensitizes human glioblastoma cells through inhibition of platelet-derived growth factor receptor

Abstract

Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.