Therapeutic suppression of constitutive and inducible JAK\STAT activation in head and neck squamous cell carcinoma

J Exp Ther Oncol. 2009;8(2):117-27.

Abstract

The oncogenic role of STAT3 has been elucidated in a number of human malignancies including leukemia, lymphoma, malignant glioma and cancers of the breast, lung, and head and neck (HNSCC). Here we show that WP1066 has profound anti-neoplastic effects in HNSCC, mediated in part by suppression of JAK2-STAT3 signaling. WP1066 inhibited constitutive and inducible STAT3 phosphorylation in both dose- and time-dependant manners. Further, the nuclear translocation of STAT3 was completely inhibited, resulting in decreased DNA binding activity. In vivo testing of WP1066 in a nude mouse orthotopic model of HNSCC demonstrated significant anti-tumor effects, with histological evidence of decreased cellular proliferation and angiogenesis. Collectively, these data suggest that WP1066 suppresses squamous cell carcinoma cell growth, in part through its effects on JAK-STAT pathways, and establishes this small molecule as potentially efficacious agent in the treatment of HNSCC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biotransformation / drug effects
  • Blotting, Western
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Immunohistochemistry
  • Indicators and Reagents
  • Male
  • Mice
  • Mice, Nude
  • Phosphorylation
  • Pyridines / pharmacology*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / biosynthesis
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Tyrphostins / pharmacology*
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Indicators and Reagents
  • Pyridines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrphostins
  • Vascular Endothelial Growth Factor A
  • WP1066