title: Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line.
abstract: Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a median survival time of less than 2 years. Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. In particular, temozolomide (TMZ)-resistant (TMZ-R) GBM is very difficult to treat, and a novel approach to overcome resistance is eagerly awaited. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the current study, the efficacy of STX-0119 was evaluated against our established TMZ-resistant U87 cell line using quantitative PCR-based gene expression analysis, in vitro assay and animal experiments. The growth inhibitory effect of STX-0119 on U87 and TMZ-R U87 cells was moderate (IC₅₀, 34 and 45 µM, respectively). In particular, STX-0119 did not show significant inhibition of U87 tumor growth; however, it suppressed the growth of the TMZ-R U87 tumor in nude mice by more than 50%, and prolonged the median survival time compared to the control group. Quantitative PCR revealed that YKL-40, MAGEC1, MGMT, several EMT genes, mesenchymal genes and STAT3 target genes were upregulated, but most of those genes were downregulated by STX-0119 treatment. Furthermore, the invasive activity of TMZ-R U87 cells was significantly inhibited by STX-0119. YKL-40 levels in TMZ-R U87 cells and their supernatants were significantly decreased by STX-0119 administration. These results suggest that STX-0119 is an efficient therapeutic to overcome TMZ resistance in recurrent GBM tumors, and could be the next promising compound leading to survival prolongation, and YKL-40 may be a possible surrogate marker for STAT3 targeting.
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ashizawa
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Miyata
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Iizuka
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Komiyama
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kume
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Omiya
authors.affiliation: Division of Pathology, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugino
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.affiliation: Division of Neurosurgery, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Nakamasa
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Division of Neurosurgery, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mitsuya
authors.affiliation: Division of Neurosurgery, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakasu
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009374:Neoplasms, Experimental; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D011804:Quinolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C559957:STX-0119; D003606:Dacarbazine; D000077204:Temozolomide