title: Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model.
abstract: Activator protein-1 (AP-1) is a transcriptional factor that regulates the expression of various genes associated with tumor invasion and migration. The purpose of our study was to assess the therapeutic effects of a novel selective AP-1 inhibitor, T-5224, in preventing lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) in an orthotopic mouse model. We assessed the effect of T-5224 on HNSCC cell invasion, migration, proliferation, and MMP activity by carrying out an in vitro study using an invasion assay, scratch assay, WST-8 assay, and gelatin zymography. We also observed morphological changes in HNSCC cells by time-lapse microscopy. Furthermore, cervical lymph node metastasis was assessed using an orthotopic tumor model of human oral squamous cell carcinoma cells (HSC-3-M3) injected in the tongue of a BALB/c nude mouse. T-5224 (150 mg/kg) or vehicle was given orally every day for 4 weeks. Animals were killed and assessed for lymph node metastasis by H&E staining of resected lymph nodes. T-5224 significantly inhibited the invasion, migration, and MMP activity of HNSCC cells in a dose-dependent manner; there was no significant influence on cell proliferation. The antimetastatic effect of T-5224 was also confirmed in our animal study. The rate of cervical lymph node metastasis in the model was 40.0% in the T-5224-treated group (n = 30) versus 74.1% in the vehicle-treated group (n = 27; P < 0.05). In conclusion, T-5224 inhibited the invasion and migration of HNSCC cells in vitro, and prevented lymph node metastasis in head and neck cancer in an animal model.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamide
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.|Department of Otorhinolaryngology-Head and Neck Surgery, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tomifuji
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Medicine, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shiozawa
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shiotani
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008807:Mice, Inbred BALB C; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000556:secondary; D023041:Xenograft Model Antitumor Assays
chemical_list: C568912:3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid; D001577:Benzophenones; D007555:Isoxazoles; D018808:Transcription Factor AP-1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Cell adhesion and motility; invasion and metastasis; metastasis inhibition; metastasis-related gene