title: Wnt/Beta-Catenin Signal Inhibitor HC-1 Sensitizes Oral Squamous Cell Carcinoma Cells to 5-Fluorouracil through Reduction of CD44-Positive Population.
abstract: BACKGROUND
  Oral squamous cell carcinoma is a prevalent and frequently lethal malignancy worldwide. Existence of treatment-resistant cancer stem cells is considered to be associated with tumor formation, recurrence and metastasis. Wnt/beta-catenin signal is one of the crucial signaling pathways for cancer stem cells. Wnt/beta-catenin signal inhibitor may reduce the population of cancer stem cells and improve therapeutic effects on the cancers.
  
  
  METHODS
  The effects of three derivatives of Wnt/beta-catenin signal inhibitors, HC-1, IC-2 and PN3-13, which we recently developed, on oral squamous cell carcinoma cell line HSC2, were examined by luciferase reporter assay, WST assay, cell sorting assay and apoptosis assay.
  
  
  RESULTS
  The reporter assay showed that these small molecule compounds reduced Wnt/beta-catenin transcriptional activity in HSC2 cells. Of these compounds, IC-2 and PN3-13 inhibited cell viability in a dose-dependent manner, whereas HC-1 did not at even higher concentrations. Notably, however, the cell-sorting assay revealed that HC-1 significantly reduces the CD44-positive population of oral squamous cell carcinoma cells, compared to other compounds without affecting cell viability. In addition, HC-1 increases the cytotoxicity of HSC2 cells to 5-fluorouracil. The combination treatment of HC-1 with 5-fluorouracil significantly increased the apoptotic cells whereas treatment by either compound did not.
  
  
  CONCLUSIONS
  These data suggest that HC-1 is an effective compound to target cancer stem cells, and the combination treatment of HC-1 and 5-fluorouracil can stimulate the tumor suppressive effect on oral squamous cell carcinoma cells.
authors: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan; †Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors: Satoshi
authors: S
authors: Yokogi
authors: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors: Toshiaki
authors: T
authors: Tsubota
authors: ‡Department of Biomedical Engineering, Faculty of Engineering, Okayama University of Science, Okayama 700-0005, Japan.
authors: Keita
authors: K
authors: Kanki
authors: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors: Junya
authors: J
authors: Azumi
authors: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors: Noriko
authors: N
authors: Itaba
authors: §Division of Instrumental Analysis, Research Center for Bioscience and Technology, Tottori University, Tottori 680-8550, Japan.
authors: Hiroyuki
authors: H
authors: Oka
authors: §Division of Instrumental Analysis, Research Center for Bioscience and Technology, Tottori University, Tottori 680-8550, Japan.
authors: Minoru
authors: M
authors: Morimoto
authors: †Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors: Kazuo
authors: K
authors: Ryoke
authors: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors: Goshi
authors: G
authors: Shiota
keywords: 5-fluorouracil; Wnt/beta-catenin signal inhibitor; cancer stem cells; oral squamous cell carcinoma; small molecule compound