title: Apigenin in combination with Akt inhibition significantly enhances thyrotropin-stimulated radioiodide accumulation in thyroid cells.
abstract: BACKGROUND
  Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation.
  
  
  METHODS
  PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies.
  
  
  RESULTS
  We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRβ(PV/PV) mice.
  
  
  CONCLUSIONS
  Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.
authors.affiliation: 1 Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University , Columbus, Ohio.
authors.forename: Aparna
authors.initials: A
authors.lastname: Lakshmanan
authors.forename: Andrea I
authors.initials: AI
authors.lastname: Doseff
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Bernard
authors.initials: B
authors.lastname: Rousset
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Sissy M
authors.initials: SM
authors.lastname: Jhiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D047310:Apigenin / Q000378:metabolism* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D019587:Dietary Supplements; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism*; D007700:Kinetics; D049990:Membrane Transport Modulators / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D019275:Radiopharmaceuticals / Q000378:metabolism; D051381:Rats; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D047310:Apigenin; D013972:Thyrotropin; D051057:Proto-Oncogene Proteins c-akt