ATPS-42INHIBITION OF STAT3 ENHANCES THE RADIOSENSITIZING EFFECT OF TEMOZOLOMIDE IN MALIGNANT GLIOMA CELLS IN VITRO AND IN VIVO

PURPOSE: Despite aggressive treatment with radiation therapy plus concurrent and adjuvant temozolomide (TMZ), the prognosis for glioblastoma remain poor. We investigated the potential of targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome of combined radiotherapy and TMZ in glioblastoma. METHODS AND MATERIALS: We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188 combined with temozolomide and radiation by in vitro clonogenic assays using two established glioblastoma cell lines (U251, U87) and two patients-derived glioblastoma cell lines (GBL12, GBL28) and in vivo studies using nude mice bearing intracranial U251 xenografts. RESULTS: Cpd188 potentiated the radiosensitizing effect of TMZ in U251 glioblastoma cell line which has high levels of p-STAT3 expression and in vitro. Increased radiosensitizing effects of TMZ were associated with the induction of apoptosis and the reversion of epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth both alone and in combination with fractionated radiation and TMZ with a trend toward improved survival rates. Immunohistochemical staining of tumor sections showed that Cpd188 decreased the expression of CD31 (a marker of endothelial proliferation), vascular endothelial growth factor, and hypoxia-inducible factor-1α, suggesting that Cpd188 also has anti-angiogenic effects. We also confirmed the radiosensitizing effect of Cpd188 of GBL28 cell line which was originated from a patient who had a glioblastoma and also was confirmed high level of STAT3 expression and unmethylated MGMT. CONCLUSION: These data indicate that Cpd188 has the potential to improve the therapeutic outcome of combined radiotherapy and TMZ in human glioblastoma, especially in patients whose tumor has a high level of STAT3 expression regardless of MGMT methylation status. Work supported by grant (#2012-0004867 u0026 #2013R1A1A2074531) from National Research Foundation, Korean Ministry of Future Creative Science to In Ah Kim.