Endocrine Abstracts (2017) 49 EP1379 | DOI: 10.1530/endoabs.49.EP1379

Effects of combination of metformin and pioglitazone on AMPK/mTOR signal pathway, p53 and apoptosis in human anaplastic thyroid cancer cells

Nilufer Ozdemir Kutbay1, Mehmet Erdogan2, Banu Sarer Yurekli2, Cansu Caliskan Kurt3, Cumhur Gunduz3 & Cigir Biray Avci3

1University of Health Sciences Gazi Yasargil Education and Training Hospital, Diyarbakir, Turkey; 2Ege University Faculty of Medicine Endocrinology Department, Izmir, Turkey; 3Ege University Faculty of Medicine Department of Medical Biology, Izmir, Turkey.

Thyroid cancer is the most common malignant tumor of the human endocrine system. Recently, its incidence has increased significantly. Anaplastic cancer constitutes 2–4% of thyroid cancers and remains aggressive. The life expectancy is 2–6 months. It is often beyond the surgical margin. External radiation therapy or chemotherapy are the treatment options. Therefore, new therapeutic approaches are needed. Peroxisome proliferator-activated receptor (PPAR) gamma is a DNA-binding nuclear hormone receptor and regulates transcription effects in cell energy metabolism. PPAR gamma agonists may inhibit tumor growth through terminal cell differentiation induction, cell cycle arrest, apoptosis induction and angiogenesis inhibition. PPAR gamma agonists show significant antitumor activities against various cancers both in vitro and in vivo. Metformin (1,1-Dimethylbiguanide) is the most widely used drug in treatment of type 2 diabetes patients. Preclinical data show its anticancer effects. The molecular mechanisms of metformin in cancer cells is still unknown. In our study, we plan to evaluate effects of combination of metformin and pioglitazone on AMPK/mTOR signal pathway, p53 and apoptosis in human anaplastic thyroid cancer cells. In C643 and SW1736 cell lines, IC50 doses of metformin and pioglitazone were found as 17.69 and 11.64 mM, and 27.12 and 23.17 μM respectively. The combination of metformin and pioglitazone was determined as additive with isobologram analyses. Both of the compounds induce apoptosis separate or in combination. Consequently, we have evaluated the down regulation of the expression levels of oncogenic AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, PIK3CA, PIK3CG, PLD1, PRKCA, RICTOR genes in MET and PIO combination treated cells. Moreover, expression levels of tumor suppressor DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MTOR, MYO1C, PTEN, ULK1, ULK2 genes were found to increase functionality. The results show that these agents can be used in the treatment of thyroid cancer as novel therapeutic agents.

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