STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell

Oncotarget. 2015 Dec 8;6(39):41944-58. doi: 10.18632/oncotarget.5986.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminosalicylic Acids / pharmacology
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Benzenesulfonates / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Self Renewal / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Fluorouracil / pharmacology
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Mice, Knockout
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Phosphorylation
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Side-Population Cells / drug effects*
  • Side-Population Cells / metabolism
  • Side-Population Cells / pathology
  • Squamous Cell Carcinoma of Head and Neck
  • Taxoids / pharmacology
  • Time Factors
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Aminosalicylic Acids
  • Benzenesulfonates
  • NSC 74859
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Taxoids
  • Docetaxel
  • Cisplatin
  • Fluorouracil