title: Antiproliferative and proapoptotic activity of sunitinib on endothelial and anaplastic thyroid cancer cells via inhibition of Akt and ERK1/2 phosphorylation and by down-regulation of cyclin-D1.
abstract: BACKGROUND
  Recent experimental evidence suggests a rationale for the use of multitarget tyrosine kinase inhibitors for the treatment of thyroid cancers. Sunitinib showed promising preliminary results against anaplastic thyroid cancer (ATC), and it has been used for some patients who are ineligible for clinical trials.
  
  
  OBJECTIVE
  The aims of this study were to investigate the in vitro and in vivo activity of sunitinib on ATC and on microvascular endothelial cells and the molecular mechanism for the observed sunitinib activity.
  
  
  METHODS
  Proliferation and apoptotic assays were performed on human dermal microvascular endothelial and on BRAF- or H-ras-mutated ATC cells (8305C and FB3, respectively) after in vitro exposure to sunitinib for 72 hours. Vascular endothelial growth factor receptor-2, epithelial growth factor receptor, ERK1/2, and Akt phosphorylation was quantified by ELISA and Western blot. Cyclin-D1 mRNA expression was evaluated by real-time PCR, and cyclin-D1 intracellular concentrations were measured by ELISA. 8305C tumor xenografts in nude mice were treated with sunitinib at 50 mg/kg/d (i.p.).
  
  
  RESULTS
  Antiproliferative and proapoptotic activity of sunitinib was observed in both endothelial and ATC cells. Phospho-vascular endothelial growth factor receptor-2 levels significantly decreased after sunitinib treatment in activated endothelial cells. Phospho-epidermal growth factor receptor, ERK1/2, and Akt phosphorylation was significantly inhibited by sunitinib treatment in endothelial and cancer cells, and cyclin-D1 mRNA and protein expression was inhibited. Sunitinib administration in vivo caused significant inhibition of tumor growth (P < .05).
  
  
  CONCLUSIONS
  Sunitinib is active in vitro and in vivo against activated endothelial and ATC cells via the inhibition of Akt and ERK1/2 phosphorylation and through the down-regulation of cyclin-D1.
authors: MD, PhD, Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors: Teresa
authors: T
authors: Di Desidero
authors: Anna
authors: A
authors: Fioravanti
authors: Paola
authors: P
authors: Orlandi
authors: Bastianina
authors: B
authors: Canu
authors: Riccardo
authors: R
authors: Giannini
authors: Nicla
authors: N
authors: Borrelli
authors: Shan
authors: S
authors: Man
authors: Ping
authors: P
authors: Xu
authors: Gabriella
authors: G
authors: Fontanini
authors: Fulvio
authors: F
authors: Basolo
authors: Robert S
authors: RS
authors: Kerbel
authors: Giulio
authors: G
authors: Francia
authors: Romano
authors: R
authors: Danesi
authors: Guido
authors: G
authors: Bocci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077210:Sunitinib; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D007211:Indoles; D011758:Pyrroles; D019938:Cyclin D1; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D000077210:Sunitinib