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

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.

• Authors: Michael E Kupferman, Arumugam Jayakumar, Ge Zhou, Tong Xie, Yasemin Dakak-Yazici, Mei Zhao, Jun Ju, Mahitosh Mandal, Samar Jasser, Timothy Madden, Jeffrey N Myers, Waldemar Priebe
• Journal: Journal of experimental therapeutics & oncology (J Exp Ther Oncol) Vol. 8 Issue 2 Pg. 117-27 ( 2009) ISSN: 1359-4117 [Print] United States
• PMID: 20192118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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