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: Daisuke Kamide, Taku Yamashita, Koji Araki, Masayuki Tomifuji, Yuya Tanaka, Shingo Tanaka, Shunichi Shiozawa, Akihiro Shiotani
• Journal: Cancer science (Cancer Sci) Vol. 107 Issue 5 Pg. 666-73 (May 2016) ISSN: 1349-7006 [Electronic] England
• PMID: 26918517 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• 3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid
• Benzophenones
• Isoxazoles
• Transcription Factor AP-1
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Animals
• Benzophenones (administration & dosage, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Shape (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Humans
• Isoxazoles (administration & dosage, pharmacology, therapeutic use)
• Lymphatic Metastasis (prevention & control)
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Mice
• Mice, Inbred BALB C
• Mouth Neoplasms (drug therapy, pathology)
• Neoplasm Invasiveness (prevention & control)
• Transcription Factor AP-1 (antagonists & inhibitors)
• Uterine Cervical Neoplasms (prevention & control, secondary)
• Xenograft Model Antitumor Assays