Inhibition of STAT3 enhances the radiosensitizing effect of temozolomide in glioblastoma cells in vitro and in vivo

Abstract

Even with aggressive treatment involving radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential for targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome in glioblastoma. We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188, combined with temozolomide and radiation using in vitro assays with two established glioblastoma cell lines (U251 and U87) and two patient-derived glioblastoma cell lines (GBL12 and GBL28) as well as in vivo studies with nude mice bearing intracranial U251 xenografts. Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cells, which have high p-STAT3 expression levels. The enhanced radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and reversion of the epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 in GBL28 cells, which were originated from a patient with a high level of STAT3 expression and unmethylated MGMT. Targeting STAT3 using Cpd188 could be a viable therapeutic approach for improving the outcome of current standard therapy in glioblastoma patients with high p-STAT3 expression.

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