Ozdemir Kutbay N.Biray Avci C.Sarer Yurekli B.Caliskan Kurt C.Shademan B.Gunduz C.Erdogan M.2024-07-222024-07-22202010956670http://akademikarsiv.cbu.edu.tr:4000/handle/123456789/13790Anaplastic cancer constitutes 1% of thyroid cancers, and it is one of the most aggressive cancers. Treatment options are external radiation therapy and/or chemotherapy. The success rate with these treatment modalities is not satisfactory. We aimed to evaluate the effects of metformin (MET) and pioglitazone (PIO) combination on apoptosis and AMP-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway in human anaplastic thyroid cancer cells. In this study, we evaluated the effects of MET and PIO individually and the combination of the two drugs on the cellular lines SW1736 and C643 ATC. Genes contained in the mTOR signaling pathway were examined using human mTOR Signalization RT2 Profiler PCR Array. In C643 and SW1736 cell lines, IC50 doses of MET and PIO were found out as 17.69 mM, 11.64 mM, 27.12 µM, and 23.17 µM. Also, the combination of MET and PIO was determined as an additive according to isobologram analyses. We have found the downregulation of the expression levels of oncogenic genes: AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, MTOR, PIK3CA, PIK3CG, PLD1, PRKCA, and RICTOR genes, in the MET and PIO combination-treated cells. In addition, expression levels of tumor suppressor genes, DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MYO1C, PTEN, ULK1, and ULK2, were found to have increased significantly. The MET + PIO combination was first applied to thyroid cancer cells, and significant reductions in the level of oncogenic genes were detected. The decreases, particularly, in AKT3, DEPTOR, EIF4E, ILK, MTOR, PIK3C, and PRKCA expressions indicate that progression can be prevented in thyroid cancer cells and these genes could be selected as therapeutic targets. © 2020 Wiley Periodicals LLCEnglishAMP-Activated Protein KinasesApoptosisCell Line, TumorDrug Therapy, CombinationGene ExpressionHumansMetforminPioglitazoneSignal TransductionThyroid Carcinoma, AnaplasticThyroid NeoplasmsTOR Serine-Threonine Kinasesakt3 proteinconserved helix loop helix ubiquitous kinaseddit4 proteinddit4l proteineif4ebp1 proteineif4ebp2 proteinfk506 binding protein 8fkbp1a proteinglycogen synthase kinase 3betahypoxia inducible factor 1alphaI kappa B kinase betainitiation factor 4Eintegrin linked kinasemammalian target of rapamycinmetforminmyo1c proteinphosphatidylinositol 3,4,5 trisphosphate 3 phosphatasephospholipase D1phosphotransferasepik3ca proteinpik3cg proteinpioglitazoneprkca proteinprotein Cdc42rapamycin-insensitive companion of mTORserine threonine protein kinase ULK1serine threonine protein kinase ULK2tumor suppressor proteinunclassified drughydroxymethylglutaryl coenzyme A reductase kinasemetforminMTOR protein, humanpioglitazonetarget of rapamycin kinaseAMPK signalinganaplastic thyroid carcinomaapoptosisArticleC-643 cell linecell viabilitycombination indexcontrolled studydown regulationdrug mechanismevaluation studygene expression levelhumanhuman cellIC50mTOR signalingSW1736 cell lineWST-1 assayapoptosiscombination drug therapydrug effectgene expressionmetabolismpathologysignal transductionthyroid carcinomathyroid tumortumor cell lineArticle10.1002/jbt.22547