Imatinib mesylate inhibits the growth of breast cancer cells mediated by PDGF-receptor-β and Akt inactivation

Abstract

20040 Background: The prognosis of patients with progressed breast cancer remains poor after intensive chemotherapy. Therefore new treatment options such as targeted therapies are needed. Imatinib Mesylate is a tyrosin kinase inhibitor targeting growth receptors like PDGF-R α and β, c-kit. These receptors and their downstream effectors trigger a cascade that regulates multiple cellular processes such as proliferation, differentiation and survival. The activity of the important downstream effector Akt leads to cell survival through inhibition of pro-apoptotic signals. We therefore evaluated the effects of Imatinib on of PDGFR β and Akt activity in breast cancer cell lines in vitro. We previously detected that Imatinib inhibits the growth of the breast cancer cell lines MDA MB 231, MCF 7, ZR 75–1 and T 47-D in vitro. Furthermore Imatinib induces apoptosis in these cell lines. Methods: To investigate effects on receptor activation, cells were stimulated with PDGF BB, the physiological ligand of PDGFR β. Phosphorylation of PDGFR β and Akt was examined after incubation with increasing concentrations of Imatinib by immunohistochemical and western blot assays. Imatinib concentrations from 2 μM to 10 μM were applied. Results: Imatinib Mesylate shows a dose dependent inhibitory effect on PDGFR β phosphorylation, determined by immunohistochemistry and western blot analysis. No changes in the expression pattern occured. The phosphorylation of the tyrosine kinase Akt can also be inhibited by Imatinib in a dose dependent manner. The expression of Akt remains also unchanged. Conclusions: It can be suggested that the growth inhibitory effect of Imatinib Mesylate on breast cancer cell lines is caused by a dose dependent decrease of activation in PDGFR β and Akt. The inhibition of Akt phosphorylation by Imatinib explains the induction of apoptosis. These interesting effects should be further validated in vivo in clinical trials. [Table: see text]