title: 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.
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Tae Jin
authors: TJ
authors: Han
authors: Department of Radiation Oncology, Medical Science Research Institute, Seoul National University Bundang Hospital, 166 Gumiro, Bundanggu, Seongnam, Kyeonggido, 13620, Republic of Korea.
authors: Bong Jun
authors: BJ
authors: Cho
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.|Department of Radiation Oncology, Medical Science Research Institute, Seoul National University Bundang Hospital, 166 Gumiro, Bundanggu, Seongnam, Kyeonggido, 13620, Republic of Korea.
authors: Eun Jung
authors: EJ
authors: Choi
authors: Department of Radiation Oncology, Medical Science Research Institute, Seoul National University Bundang Hospital, 166 Gumiro, Bundanggu, Seongnam, Kyeonggido, 13620, Republic of Korea.
authors: Dan Hyo
authors: DH
authors: Kim
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Sang Hyuk
authors: SH
authors: Song
authors: Cancer Research Institute, School of Medicine, Seoul National University, Seoul, Republic of Korea.|Department of Neurosurgery, School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Sun Ha
authors: SH
authors: Paek
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea. inah228@snu.ac.kr.|Department 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.|Cancer Research Institute, School of Medicine, Seoul National University, Seoul, Republic of Korea. inah228@snu.ac.kr.
authors: In Ah
authors: IA
authors: Kim
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D019817:Benzoic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002465:Cell Movement / Q000187:drug effects; D015254:DNA Modification Methylases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011827:Radiation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: C000625764:4-((3-(carboxymethylsulfanyl)-4-hydroxy-1-naphthyl)sulfamoyl)benzoic acid; D017304:Annexin A5; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011838:Radiation-Sensitizing Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; D062366:para-Aminobenzoates; D003606:Dacarbazine; D019817:Benzoic Acid; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: Glioblastoma; Radiosensitization; STAT3; Temozolomide