Abstract
BackgroundRadiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines.MethodsGBM cell lines U251 and U87 were treated with YM155 to assess cytotoxicity and activity of the molecule in vitro. Nude mice were implanted with cells to generate orthotopic xenografts for in vivo studies. Response of cells to treatment was examined using cell viability, immunofluorescence, wound healing, and the Transwell invasion assay. Molecules potentially mediating response were examined through western blot analysis, phospho-kinase arrays, and qPCR. Cells were transfected with siRNA knockdown and gene expression constructs to identify molecular mediators of response.ResultsYM155 reduced viability of U251 and U87 cells and enhanced radiosensitivity through inhibition of homologous recombination. Besides, YM155 decreased invasion caused by radiation and led to expression changes in molecular markers associated with EMT. STAT3 was one of 10 molecules identified on a phosphokinase array exhibiting significant change in phosphorylation under YM155 treatment. Transfection with STAT3 siRNAs or expression constructs demonstrated that EMT changes were achieved by inhibiting the phosphorylation of STAT3 and were survivin-independent. Finally, combining YM155 and radiation in orthotopic xenografts reduced growth and prolonged overall survival of animals.ConclusionsYM155 decreased radiation-induced invasion in GBM cell lines in vitro and in vivo through inhibition of STAT3.
Highlights
Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM)
We found that YM155 reversed epithelial–mesenchymal transition (EMT) in glioma cells and prevented radiationinduced in vitro and in vivo invasion, and that YM155 might elicit these activities through inhibition of STAT3
YM155 inhibits proliferation of GBM cells To begin to understand whether the drug elicited antitumor effects in glioma cells, U251 and U87 cell lines were treated with increasing concentrations of YM155, and cell viability and proliferation were assessed
Summary
Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Current management is based on cytoreduction through a combination of surgery, radiation therapy, and chemotherapy. Despite this multidisciplinary approach to treatment, the prognosis of patients with GBM remains poor with a median overall survival of 9–15 months and a 2-year survival rate of 9–26% [2]. Radiotherapy, which kills cancer cells by causing DNA damage, is a highly cost-effective single-modality treatment [3]. Studies have reported that radiation can induce even more aggressive behavior in cancer cells [4,5,6], which further contributes to its failure in the treatment of GBM patients.
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