In-vitro effects of the tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation

Glioblastoma (GBL) is the most malignant brain tumour in adults, causing the death of most patients within 9-12 months of diagnosis. Treatment is based on a combination of surgery, radiation therapy, and chemotherapy. With these treatment modalities, however, responses are extremely poor, so identification of novel treatment strategies is highly warranted. Platelet-derived growth factors (PDGF) and their receptors are commonly coexpressed in GBL, suggesting that stimulation of autocrine PDGF receptors may contribute to their growth. Interest in these receptors as drug target for glioblastoma treatment has increased with the clinical availability of the PDGFR kinase inhibitor antagonist imatinib mesylate (STI571). In this study, T98G and A172 human GBL cell lines were analysed for their sensitivity to treatment with imatinib. In particular, we focussed our attention on analysis of DNA distribution by flow cytometry at different times of incubation with different imatinib concentrations (1-30 mu M). Our results show that imatinib induces growth arrest in T98G and A172 cells in the G(0)/G(1) phase of the cell cycle, at all the concentrations tested, as early as 24 h after treatment. However we have also seen, by means of annexin V staining, that at 20 and 30 mu M concentrations, in concomitance with a significant growth arrest in the G(0)/G(1) phase, there is an increase of apoptotic cells 48 h after treatment, suggesting that imatinib at low concentrations (1-10 mu M) could act as a cytostatic agent whereas at high concentrations (20, 30 mu M) it mainly behaves as a cytotoxic agent.