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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. 

Author information

Han TJ1, Cho BJ2, Choi EJ1,2, Kim DH2, Song SH1, Paek SH3,4, Kim IA5,6,7.​

1Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.

2Department of Radiation Oncology, Medical Science Research Institute, Seoul National University Bundang Hospital, 166 Gumiro, Bundanggu, Seongnam, Kyeonggido, 13620, Republic of Korea.

3Cancer Research Institute, School of Medicine, Seoul National University, Seoul, Republic of Korea.

4Department of Neurosurgery, School of Medicine, Seoul National University, Seoul, Republic of Korea.

5Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea. inah228@snu.ac.kr.

6Department of Radiation Oncology, Medical Science Research Institute, Seoul National University Bundang Hospital, 166 Gumiro, Bundanggu, Seongnam, Kyeonggido, 13620, Republic of Korea. inah228@snu.ac.kr.

7Cancer Research Institute, School of Medicine, Seoul National University, Seoul, Republic of Korea. inah228@snu.ac.kr.