Selective Activator Protein-1 Inhibitor T-5224 Prevents Lymph Node Metastasis in an Oral Cancer Model

Summary

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 matrix-metalloproteinase activity by performing 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 administered orally every day for 4 weeks. Animals were sacrificed and assessed for lymph-node metastasis by hematoxylin-eosin staining of resected lymph nodes. T-5224 significantly inhibited the invasion, migration, and matrix-metalloproteinase activity of HNSCC cells in a dose-dependent manner; there was no significant influence on cell proliferation. The anti-metastatic 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.

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