title: Cell Death Induction by the Indirubin Derivative 7BIO and the BH3 Mimetic Drugs ABT-737 and GX15-070 in Medullary Thyroid Carcinoma Cells.
abstract: OBJECTIVE
  Patients with advanced and metastasized medullary thyroid carcinoma are difficult to treat since tumor cells do not respond to chemotherapeutic treatment and external radiation. Direct induction of cell death is a new therapeutic approach to therapy-resistant tumor cells. In this study we analyzed the effect of the indirubin-derivative 7BIO and the BH3 mimetic drugs ABT-737 and GX15-070 on cell death induction of TT medullary thyroid carcinoma cells.
  
  
  METHODS
  TT medullary thyroid carcinoma cell line was treated with 7BIO, ABT-737 and GX15-070. Cell viability was analyzed by MTT assay, while cell death was determined by caspase 3/7 activity, measurement of caspase cleavage products and lactate dehydrogenase liberation assay. LC3B cleavage was analyzed by western blot.
  
  
  RESULTS
  Incubation with all 3 drugs efficiently decreased the number of viable TT cells with IC50 values of 4.1 µM (7BIO), 0.19 µM (ABT-737) and 0.23 µM (GX15-070). The BH3 mimetic ABT-737 caused an apoptotic cell death with caspase activation as expected, while 7BIO- and GX15-070-treatment led to a mixed kind of cell death, where caspase activation was detected but had no effect on viability of TT cells. LC3 conversion as a biochemical marker of autophagic cell death was observed after GX15-070 treatment while LDH release pointed to involvement of necrosis after treatment with all 3 drugs.
  
  
  CONCLUSIONS
  The BH3 mimetic drugs ABT-737 and GX15-070 efficiently killed TT medullary thyroid carcinoma cells with low IC50 values, while the indirubin-derivative 7BIO was also effective but with a higher IC50 value. Although the exact kind of cell death and target molecules of 7BIO and GX15-070 are not yet defined, direct induction of cell death may be a new therapeutic option in medullary thyroid carcinoma cells.
authors: Department of Endocrinology and Metabolism, and Division of Laboratory Research, University Hospital Essen, Essen, Germany.
authors: M
authors: M
authors: Broecker-Preuss
authors: Department of Endocrinology and Metabolism, and Division of Laboratory Research, University Hospital Essen, Essen, Germany.
authors: N
authors: N
authors: Becher-Boveleth
authors: Department of Endocrinology and Metabolism, and Division of Laboratory Research, University Hospital Essen, Essen, Germany.
authors: K
authors: K
authors: Mann
mesh_terms: D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018716:Molecular Mimicry; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy*
chemical_list: C501332:ABT-737; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; D007211:Indoles; D009596:Nitrophenols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C520962:obatoclax; C027185:indirubin