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.
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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)
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Chemical References |
- Angiogenesis Inhibitors
- Antineoplastic Agents
- Indicators and Reagents
- Pyridines
- STAT3 Transcription Factor
- STAT3 protein, human
- Tyrphostins
- Vascular Endothelial Growth Factor A
- WP1066
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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)
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