title: Chemotherapeutic effects of luteolin on radio-sensitivity enhancement and interleukin-6/signal transducer and activator of transcription 3 signaling repression of oral cancer stem cells.
abstract: OBJECTIVE
  Previously, we successfully identified oral cancer stem cells (OCSC) displaying enhanced stemness and tumorigenic potentials. In the study, we investigated the chemotherapeutic effect of the flavonoid luteolin, commonly found in fruits and vegetables, on targeting OCSC.
  
  
  METHODS
  Oralspheres was applied to isolate OCSC. aldehyde dehydrogenase 1 activity and CD44 positivity of OCSC with luteolin treatment were assessed by flow cytometry analysis. Radio-sensitivity of OCSC treated with luteolin was examined. Invasion and colony-forming assays were performed to assess oncogenicity in OCSC. The expression of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) was examined by enzyme-linked immunosorbent assay and western blot analysis.
  
  
  RESULTS
  We showed that luteolin effectively inhibited the proliferation rate, self-renewal, aldehyde dehydrogenase 1 activity, and CD44 positivity of OCSC but did not cause significant cytotoxicity of normal epithelial cells. Moreover, luteolin restored radio-sensitivity in OCSC. Combined treatment with luteolin and radiation displayed synergistic effect on invasiveness and clonogenicity of OCSC. Mechanistically, treatment of luteolin resulted in inactivation of IL-6/STAT3 signaling.
  
  
  CONCLUSIONS
  These results suggest that combined treatment of luteolin and radiation therapy can attenuate tumorigenicity of OCSC through IL-6/STAT3 signaling inactivation.
authors.affiliation: Department of Nuclear Medicine, Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chia-Yi, Taiwan; Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Dom-Gene
authors.initials: DG
authors.lastname: Tu
authors.affiliation: Department of Oral and Maxillofacial Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Lin
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yu
authors.initials: CY
authors.lastname: Peng
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: linperi@tmd.ac.jp.
authors.forename: Taichen
authors.initials: T
authors.lastname: Lin
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: tao2008@csmu.edu.tw.
authors.forename: Chuan-Hang
authors.initials: CH
authors.lastname: Yu
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D063646:Carcinogenesis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis; D047311:Luteolin / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D050697:Retinal Dehydrogenase / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D015850:Interleukin-6; D007527:Isoenzymes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D047311:Luteolin
keywords: cancer stem cells; luteolin; oral carcinomas; radio-sensitivity