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A novel tyrosine kinase inhibitor can augment radioactive iodine uptake through endogenous sodium/iodide symporter (NIS) expression in anaplastic thyroid cancer.
一种新型酪氨酸激酶抑制剂可以通过内源性钠/碘转运体 (NIS) 在未分化甲状腺癌中的表达增加放射性碘摄取。

摘要

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 de-differentiation 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. Here, we identified a new TKI and investigated its effects on cell re-differentiation, 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 timepoints. Concentrations of 12.5 µM 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. Additionally, 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 pre-treatment 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.

译文

背景放射性碘 (RAI) 治疗是甲状腺癌治疗的重要策略。然而,间变性甲状腺癌 (ATC) 是一种罕见的恶性肿瘤,它表现出严重的去分化特征,同时缺乏碘化钠协同转运体 (NIS) 的表达和功能。因此,RAI 治疗是无效的,并有助于这些患者的不良预后。最近,小分子酪氨酸激酶抑制剂 (TKIs) 被用于治疗甲状腺癌患者,以恢复 NIS 的表达和功能以及 RAI 摄取能力。然而,迄今为止报道的大多数结果与分化型甲状腺癌有关。在此,我们鉴定了一种新的 TKI,并研究了它对 ATC 中细胞再分化、 NIS 功能和 RAI 治疗的影响。方法我们鉴定了一种新的 TKI,“5-(5-{4 H,5 H,6h-环戊烯 [b] thiophen-2-yl}-1,3,4-恶二唑-2-基)-1-甲基-1, 2-二氢吡啶-2-酮 ”(CTOM-DHP) 使用高通量筛选系统。CTOM-DHP 在不同浓度和时间点暴露于 8505C ATC 细胞。选择 12.5 μ m 和 25 μ m 的浓度以及 72 小时的孵育时间作为后续 NIS 启动子检测和 NIS mRNA 和蛋白表达实验的条件。此外,我们检测了 CTOM-DHP 处理后碘化物代谢的相关因素,以及介导 CTOM-DHP 对内源性 NIS 表达影响的信号通路。CTOM-DHP 预处理引起的 RAI 摄取和 131I 细胞毒性效应也在体外和体内进行了评估。结果启动子试验以及 mRNA 和蛋白表达分析证实,用 CTOM-DHP 处理 8505C ATC 细胞可以增强 NIS 表达。此外,CTOM-DHP 治疗可以显著增加与碘代谢相关的其他甲状腺特异性蛋白和甲状腺转录因子的表达。NIS 功能的增强通过增加 125I 摄取和 131I 细胞毒性来证明。内源性 NIS 表达增加与 PI3K/Akt 和 MAPK 信号通路的抑制有关。体内结果也证明了 NIS 启动子活性和 RAI 亲和力的增加是对 CTOM-DHP 处理的响应。此外,131i 介导的治疗效果在肿瘤异种移植小鼠模型中优先得到改善。结论 CTOM-DHP 是本研究中发现的一种新的 TKI,它能增强内源性 NIS 的表达,因此是一种有前途的在 ATC 中恢复 RAI 亲和力的化合物。

Thyroid Cancer

内分泌 甲状腺 疾病
概述  :  

与其他癌症相比,甲状腺癌相对罕见。甲状腺癌通常是可治疗的,并且通常通过手术治愈,如果有必要,可选择放射性碘治疗。即使癌症的诊断是可怕的,但大多数乳头状和滤泡性甲状腺癌患者的预后通常也很好。诊断方法甲状腺结节的细针穿刺活检的结果可以提示甲状腺癌的诊断,并且可以通过手术切除结节后确定。虽然甲状腺结节很常见,但不到十分之一的甲状腺结节是甲状腺癌。治疗方法手术:分化型甲状腺癌的手术范围将取决于肿瘤的大小以及肿瘤是否局限于甲状腺。手术后,大多数患者需要在其余生中服用甲状腺激素。通常,甲状腺癌仅通过手术

thyroid   英 /'θaɪrɒɪd/   美 /'θaɪrɔɪd/

       n. 甲状腺;甲状软骨;甲状腺剂;adj. 甲状腺的;盾状的

同根词   thyroidectomy n. [外科] 甲状腺切除术

       I believe that thyroid hormone treatment should not be given to all overweight subjects. 我相信甲状腺激素治疗并不适用于所有的肥胖病人。

 

cancer   英 /'kænsə/  美 /kænsə/

       n. 癌症;恶性肿瘤

同根词   cancerous adj. 癌的;生癌的;像癌的

       However, they appear to be at lower risk of death from cancer. 然而,面对癌症死亡,他们似乎有一个较低的风险。

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