However, the eff ect of SU6656 on cell survival in ATC cells has not been evaluated. p21/WAF1 modulates survival and growth via a p53-dependent or-independent pathway [ 13 ]. p21 mediates cell cycle arrest by impediment of p53-dependent cyclin dependent kinases, while it represses cell death by hindrance of p53dependent or-independent pathway [ 13 ]. p21 is present in 40 % of patients with papillary thyroid carcinoma (PTC), 7 % of patients with poorly differentiated thyroid carcinoma, and 0 % of patients with ATC, and its levels are reduced in PTC cells which have a tendency to undergo early metastasis [ 14 , 15 ]. Even though changes in p21 caused by some agents are related to survival of human cancer cells, the relationship of p21 with cell survival in SU6656-treated ATC cells has not been clarifi ed [ 16-18 ]. PI3K/Akt signaling is involved in the control of multiple cellular processes including survival, growth, proliferation, diff erentiation, and migration [ 19 ] .

SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells. After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416.

Our results demonstrate that gemigliptin induces cytotoxicity in thyroid carcinoma cells. Moreover, gemigliptin has a synergistic activity with PXD101 in the induction of cell death through involvement of Bcl2 family proteins, xIAP and survivin as well as mediation of Akt and AMPK in thyroid carcinoma cells.