경북의대 / 오지민, 안병철*
Abstract
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.
Author information
Oh JM1,2, Baek SH1,2, Gangadaran P1,2,3, Hong CM1,2, Rajendran RL1,2,3, Lee HW1,2, Zhu L1,2, Gopal A1,2, Kalimuthu S1,2, Jeong SY1,2, Lee SW1,2, Lee J1,2, Ahn BC1,2,3.
1
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
2
Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea.
3
BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
편집위원
방사성요오드 불응성 갑상선암은 예후가 불량하며, 이를 극복하기 위해 다양한 갑상선재분화 요법이 시도되고 있다. 해당 연구는 갑상선암의 재분화를 높이는 새로운 tyrosine kinase inhibitor를 선별하고 이를 이용한 갑상선암 재분화 및 방사성요오드 치료를 다시 적용하는 전임상연구이다. 검색된 CTOM-DHP는 MAPK 신호전달 체계를 억제하여 갑상선 특이 단백의 발현을 증가시키고 이차적으로 갑상선암세포내로 방사성요오드 축적을 증가시키는 것을 확인함. 갑상선암 관련 연구자, 방사성요오드 치료 핵의학의사에게 관심을 끌 논문으로 생각됨.
2020-05-28 14:04:34