Abstract
Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC.
Keywords:
S3I-201; STAT3; cancer stem cell; chemotherapy; head neck squamous cell carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminosalicylic Acids / pharmacology
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Benzenesulfonates / pharmacology*
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Self Renewal / drug effects
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Cell Survival / drug effects
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Cisplatin / pharmacology
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Docetaxel
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Dose-Response Relationship, Drug
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Fluorouracil / pharmacology
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Humans
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Mice, Knockout
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Mice, Nude
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Phenotype
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Phosphorylation
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / metabolism
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Side-Population Cells / drug effects*
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Side-Population Cells / metabolism
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Side-Population Cells / pathology
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Squamous Cell Carcinoma of Head and Neck
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Taxoids / pharmacology
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Time Factors
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Aminosalicylic Acids
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Benzenesulfonates
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NSC 74859
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STAT3 Transcription Factor
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STAT3 protein, human
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Taxoids
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Docetaxel
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Cisplatin
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Fluorouracil