A Novel Tyrosine Kinase Inhibitor Can Augment Radioactive Iodine Uptake Through Endogenous Sodium/Iodide Symporter Expression in Anaplastic Thyroid Cancer

• DOI: 10.1089/thy.2018.0626
• Publication Date: 2020-01-13T09:12:17Z
• Authors: Ji Min Oh; Se Hwan Baek; Prakash Gangadaran; Chae Moon Hong; Ramya Lakshmi Raj...; Ho Won Lee; Liya Zhu; Arunnehru Gopal; Senthilkumar Kali...; Shin Young Jeong; Sang-Woo Lee; Jaetae Lee; Byeong-Cheol Ahn
• Keywords: Sodium-iodide symporter; Anaplastic thyroid cancer

Background: Radioactive iodine (RAI) therapy is an important strategy in the treatment of thyroid cancer. However, anaplastic cancer (ATC), a rare malignancy, exhibits severe dedifferentiation characteristics along with lack sodium iodide symporter (NIS) expression and function. Therefore, RAI ineffective contributes toward poor prognosis these patients. Recently, small-molecule tyrosine kinase inhibitors (TKIs) have been used to treat patients for restoring NIS function uptake capacity. most results reported thus far are associated differentiated In this study, we identified new TKI investigated its effects on cell redifferentiation, function, ATC. Methods: We TKI, "5-(5-{4H, 5H,6H-cyclopenta[b]thiophen-2-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-1,2-dihydropyridin-2-one" (CTOM-DHP), using high-throughput screening system. CTOM-DHP was exposed 8505C ATC cells at different concentrations time points. Concentrations 12.5 25 μM incubation 72 hours were chosen as conditions subsequent promoter assays mRNA protein experiments. addition, examined factors related metabolism after well signaling pathways mediating endogenous expression. 131I cytotoxicity caused by pretreatment also evaluated vitro vivo. Results: Promoter analyses confirmed that augmented CTOM-DHP. Moreover, robustly increased other thyroid-specific proteins transcription metabolism. Enhancement demonstrated increase 125I cytotoxicity. Increased inhibition PI3K/Akt MAPK pathways. vivo activity avidity response treatment. Furthermore, 131I-mediated therapeutic preferentially improved tumor xenograft mice model. Conclusions: CTOM-DHP, enhances thereby promising compound