title: Effect of perioperative treatment with a hypoxia-inducible factor-1-alpha inhibitor in an orthotopic surgical mouse model of thyroid cancer.
abstract: OBJECTIVE
  Despite an excellent prognosis, certain patients with thyroid cancer suffer from locally invasive disease that cannot be controlled by conventional therapy. Our previous study suggested that hypoxia inducible factor-1-alpha (HIF1α) might be an important marker for the identification of and a treatment target of intractable thyroid cancer. Therefore, in the present study, we established an orthotopic mouse surgical model of thyroid cancer that mimics the clinical setting, and evaluated the effect of perioperative treatment with a HIF1α inhibitor.
  
  
  METHODS
  Seven thyroid cancer cell lines (SNU-790, BCPAP, KTC1, TPC1, TPC1-M, KTC2, and FRO) and four HIF1α inhibitors (echinomycin, LAQ824, temsirolimus, and vorinostat) were used in the present study. Expression of HIF1α and related proteins was evaluated in all cell lines; immunoblotting and cell proliferation assays were conducted; and echinomycin was validated in an orthotopic surgical mouse model.
  
  
  RESULTS
  Nuclear expression of HIF1α increased in tumorigenic cell lines, while HIF1α inhibitors inhibited proliferation and colony formation. In the orthotopic surgical model, the group treated with surgery and the echinomycin-treatment group showed a highly significant survival gain (p=0.001) compared to the control group.
  
  
  CONCLUSIONS
  The highly significant survival gain resulting from their use in perioperative adjuvant treatment in vivo and their anticancer effect in vitro suggest that HIF1α inhibitors might be candidates for perioperative adjuvant chemotherapy for thyroid cancer. Combining adjuvant HIF1α inhibitor chemotherapy with surgery might be an effective therapeutic strategy for thyroid cancer that is refractory to conventional treatments.
authors: Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University Hospital, Busan, Republic of Korea Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors: Wonjae
authors: W
authors: Cha
authors: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Dong-Wook
authors: DW
authors: Kim
authors: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Sung Dong
authors: SD
authors: Kim
authors: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Eun-Hui
authors: EH
authors: Jeon
authors: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Woo-Jin
authors: WJ
authors: Jeong
authors: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Seoul National University College of Medicine, Seoul, Republic of Korea ahnsh30@snu.ac.kr.
authors: Soon-Hyun
authors: SH
authors: Ahn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059035:Perioperative Period; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077337:Vorinostat
chemical_list: C497443:Hif1a protein, mouse; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477361:LAQ824; D000077337:Vorinostat
keywords: HIF1α inhibitor; Thyroid cancer; adjuvant chemotherapy; echinomycin; molecular targeted therapy; orthotopic mouse model