التفاصيل البيبلوغرافية
| العنوان: |
A Novel Tyrosine Kinase Inhibitor Can Augment Radioactive Iodine Uptake Through Endogenous Sodium/Iodide Symporter Expression in Anaplastic Thyroid Cancer. |
| المؤلفون: |
Oh, Ji Min, Baek, Se Hwan, Gangadaran, Prakash, Hong, Chae Moon, Rajendran, Ramya Lakshmi, Lee, Ho Won, Zhu, Liya, Gopal, Arunnehru, Kalimuthu, Senthilkumar, Jeong, Shin Young, Lee, Sang-Woo, Lee, Jaetae, Ahn, Byeong-Cheol |
| المصدر: |
Thyroid; Apr2020, Vol. 30 Issue 4, p501-518, 18p |
| مصطلحات موضوعية: |
IODINE isotopes, ANAPLASTIC thyroid cancer, PROTEIN-tyrosine kinases, KINASE inhibitors, TREATMENT effectiveness, SODIUM iodide, THYROID cancer |
| مستخلص: |
Background: Radioactive iodine (RAI) therapy is an important strategy in the treatment of thyroid cancer. However, anaplastic thyroid cancer (ATC), a rare malignancy, exhibits severe dedifferentiation characteristics along with a lack of sodium iodide symporter (NIS) expression and function. Therefore, RAI therapy is ineffective and contributes toward poor prognosis of these patients. Recently, small-molecule tyrosine kinase inhibitors (TKIs) have been used to treat thyroid cancer patients for restoring NIS expression and function and RAI uptake capacity. However, most results reported thus far are associated with differentiated thyroid cancer. In this study, we identified a new TKI and investigated its effects on cell redifferentiation, NIS function, and RAI therapy in ATC. Methods: We identified a new 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 a high-throughput screening system. CTOM-DHP was exposed to 8505C ATC cells at different concentrations and time points. Concentrations of 12.5 and 25 μM and an incubation time of 72 hours were chosen as the conditions for subsequent NIS promoter assays and NIS mRNA and protein expression experiments. In addition, we examined factors related to iodide metabolism after CTOM-DHP treatment as well as the signaling pathways mediating the effects of CTOM-DHP on endogenous NIS expression. RAI uptake and 131I cytotoxicity effects caused by CTOM-DHP pretreatment were also evaluated in vitro and in vivo. Results: Promoter assays as well as mRNA and protein expression analyses confirmed that NIS expression was augmented by treatment of 8505C ATC cells with CTOM-DHP. Moreover, CTOM-DHP treatment robustly increased the expression of other thyroid-specific proteins and thyroid transcription factors related to iodide metabolism. Enhancement of NIS function was demonstrated by an increase in 125I uptake and 131I cytotoxicity. Increased endogenous NIS expression was associated with the inhibition of PI3K/Akt and MAPK signaling pathways. In vivo results also demonstrated an increase in NIS promoter activity and RAI avidity in response to CTOM-DHP treatment. Furthermore, 131I-mediated therapeutic effects preferentially improved in a tumor xenograft mice model. Conclusions: CTOM-DHP, a new TKI identified in this study, enhances endogenous NIS expression and thereby is a promising compound for restoring RAI avidity in ATC. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
