PMID- 32589349
OWN - NLM
STAT- MEDLINE
DCOM- 20210608
LR  - 20211204
IS  - 1099-0461 (Electronic)
IS  - 1095-6670 (Linking)
VI  - 34
IP  - 10
DP  - 2020 Oct
TI  - Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR 
      signaling pathway in human anaplastic thyroid cancer cells.
PG  - e22547
LID - 10.1002/jbt.22547 [doi]
AB  - Anaplastic 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 RT(2) Profiler PCR Array. In C643 and SW1736 cell lines, 
      IC(50) doses of MET and PIO were found out as 17.69 mM, 11.64 mM, 27.12 microM, and 
      23.17 microM. 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.
CI  - (c) 2020 Wiley Periodicals LLC.
FAU - Ozdemir Kutbay, Nilufer
AU  - Ozdemir Kutbay N
AD  - Department of Endocrinology, Faculty of Medicine, Celal Bayar University, Manisa, 
      Turkey.
FAU - Biray Avci, Cigir
AU  - Biray Avci C
AUID- ORCID: 0000-0001-8251-4520
AD  - Department of Medical Biology, Ege University Medical School, Izmir, Turkey.
FAU - Sarer Yurekli, Banu
AU  - Sarer Yurekli B
AD  - Department of Endocrinology, Ege University Medical School, Izmir, Turkey.
FAU - Caliskan Kurt, Cansu
AU  - Caliskan Kurt C
AD  - Department of Medical Biology, Ege University Medical School, Izmir, Turkey.
FAU - Shademan, Behrouz
AU  - Shademan B
AUID- ORCID: 0000-0003-2663-723X
AD  - Department of Medical Biology, Ege University Medical School, Izmir, Turkey.
FAU - Gunduz, Cumhur
AU  - Gunduz C
AD  - Department of Medical Biology, Ege University Medical School, Izmir, Turkey.
FAU - Erdogan, Mehmet
AU  - Erdogan M
AD  - Department of Endocrinology, Ege University Medical School, Izmir, Turkey.
LA  - eng
GR  - Ege Universitesi/
GR  - This study relies on Ege University coordinatorship of scientific research 
      projects (2014-TIP-013) Account Holder: Mehmet Erdogan/
PT  - Journal Article
DEP - 20200626
PL  - United States
TA  - J Biochem Mol Toxicol
JT  - Journal of biochemical and molecular toxicology
JID - 9717231
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Apoptosis/*drug effects
MH  - Cell Line, Tumor
MH  - Drug Therapy, Combination
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Metformin/administration & dosage/*pharmacology
MH  - Pioglitazone/administration & dosage/*pharmacology
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Thyroid Carcinoma, Anaplastic/*metabolism/pathology
MH  - Thyroid Neoplasms/*metabolism/pathology
OTO - NOTNLM
OT  - apoptosis
OT  - cell lines
OT  - metformin
OT  - pioglitazone
OT  - signaling pathway
OT  - thyroid cancer
EDAT- 2020/06/27 06:00
MHDA- 2021/06/09 06:00
CRDT- 2020/06/27 06:00
PHST- 2020/02/03 00:00 [received]
PHST- 2020/04/28 00:00 [revised]
PHST- 2020/05/29 00:00 [accepted]
PHST- 2020/06/27 06:00 [pubmed]
PHST- 2021/06/09 06:00 [medline]
PHST- 2020/06/27 06:00 [entrez]
AID - 10.1002/jbt.22547 [doi]
PST - ppublish
SO  - J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 
      Jun 26.