Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, and is rapidly progressive with few curative treatment options. Sorafenib (Nexavar, BAY43-9006), a multi-kinase inhibitor, blocks proliferation and induces apoptosis in a variety of tumor cells. Here, we report that sorafenib (\#8804; 10 µM) strongly inhibited cell proliferation and induced apoptosis in two established cell lines (U87 and U251) and two low-passage primary cultures (PBT015 and PBT022) from human glioblastomas. Sorafenib inhibited phosphorylation of STAT3 (Signal Transducers and Activators of Transcription 3) at Tyr 705 and STAT3 DNA-binding activity in both cell lines and primary cultures. By contrast, AKT (protein kinase B) and MAPK (ERK1/2) were differentially inhibited by sorafenib in these cells. Two key cyclins (D and E) were down-regulated by sorafenib in both cell lines and primary cultures, and their expression levels were correlated with growth arrest induced by sorafenib. Moreover, sorafenib inhibited expression of Mcl-1, an anti-apoptosis protein, and induced apoptosis. Our data demonstrate that inhibition of STAT3 signaling and downstream target genes are associated with growth arrest and induction of apoptosis in glioblastoma cell lines and primary cultures. These findings provide a rationale for treatment of malignant gliomas with sorafenib.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5627.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009