title: Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma.
abstract: Signal transducer and activator of transcription (STAT) 3, a member of a family of DNA-binding molecules, is a potential target in the treatment of cancer. The highly phosphorylated STAT3 in cancer cells contributes to numerous physiological and oncogenic signaling pathways. Furthermore, a significant association between STAT3 signaling and glioblastoma multiforme stem-like cell (GBM-SC) development and maintenance has been demonstrated in recent studies. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the present study, we focused on cancer stem-like cells derived from recurrent GBM patients and investigated the efficacy of STX-0119. Three GBM stem cell lines showed many stem cell markers such as CD133, EGFR, Nanog, Olig2, nestin and Yamanaka factors (c-myc, KLF4, Oct3/4 and SOX2) compared with parental cell lines. These cell lines also formed tumors in vivo and had similar histological to surgically resected tumors. STAT3 phosphorylation was activated more in the GBM-SC lines than serum-derived GB cell lines. The growth inhibitory effect of STX-0119 on GBM-SCs was moderate (IC50 15-44 µM) and stronger compared to that of WP1066 in two cell lines. On the other hand, the effect of temozolomide was weak in all the cell lines (IC50 53-226 µM). Notably, STX-0119 demonstrated strong inhibition of the expression of STAT3 target genes (c-myc, survivin, cyclin D1, HIF-1α and VEGF) and stem cell-associated genes (CD44, Nanog, nestin and CD133) as well as the induction of apoptosis in one stem-like cell line. Interestingly, VEGFR2 mRNA was also remarkably inhibited by STX-0119. In a model using transplantable stem-like cell lines in vivo GB-SCC010 and 026, STX-0119 inhibited the growth of GBM-SCs at 80 mg/kg. STX-0119, an inhibitor of STAT3, may serve as a novel therapeutic compound against GBM-SCs even in temozolomide-resistant GBM patients and has the potential for GBM-SC-specific therapeutics in combination with temozolomide plus radiation therapy.
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ashizawa
authors.forename: Haruo
authors.initials: H
authors.lastname: Miyata
authors.forename: Akira
authors.initials: A
authors.lastname: Iizuka
authors.forename: Masaru
authors.initials: M
authors.lastname: Komiyama
authors.forename: Chie
authors.initials: C
authors.lastname: Oshita
authors.forename: Akiko
authors.initials: A
authors.lastname: Kume
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nogami
authors.forename: Mika
authors.initials: M
authors.lastname: Yagoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ito
authors.forename: Takuma
authors.initials: T
authors.lastname: Oishi
authors.forename: Reiko
authors.initials: R
authors.lastname: Watanabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Mitsuya
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Toshio
authors.initials: T
authors.lastname: Furuya
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okawara
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakasu
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Akiyama
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010069:Oxadiazoles / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D010069:Oxadiazoles; D011804:Quinolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C559957:STX-0119