Purpose

Non-medullary thyroid cancer (NMTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). However, in a subset of NMTC patients tumor dedifferentiation occurs, leading to RAI resistance. Digoxin has been demonstrated to restore iodide uptake capacity in vitro in poorly differentiated and anaplastic NMTC cells, termed redifferentiation. The aim of the present study was to investigate the in vivo effects of digoxin in TPO-Cre/LSL-Braf^V600E mice and digoxin-treated NMTC patients.

Methods

Mice with thyroid cancer were subjected to 3D ultrasound for monitoring tumor growth and ¹²⁴I PET/CT for measurement of intratumoral iodide uptake. Post-mortem analyses on tumor tissues comprised gene expression profiling and measurement of intratumoral autophagy activity. Through PALGA (Dutch Pathology Registry), archived tumor material was obtained from 11 non-anaplastic NMTC patients who were using digoxin. Clinical characteristics and tumor material of these patients were compared to 11 matched control NMTC patients never treated with digoxin.

Results

We found that in mice, tumor growth was inhibited and ¹²⁴I accumulation was sustainably increased after short-course digoxin treatment. Post-mortem analyses revealed that digoxin treatment increased autophagy activity and enhanced expression of thyroid-specific genes in mouse tumors compared to vehicle-treated mice. Digoxin-treated NMTC patients exhibited significantly higher autophagy activity and a higher differentiation status as compared to matched control NMTC patients, and were associated with favourable clinical outcome.

Conclusions

These in vivo data support the hypothesis that digoxin may represent a repositioned adjunctive treatment modality that suppresses tumor growth and improves RAI sensitivity in patients with RAI-refractory NMTC.

中文翻译：

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地高辛治疗重新激活体内放射性碘摄取并与非髓样甲状腺癌的良好临床结果相关

目的

非髓样甲状腺癌 (NMTC) 治疗基于甲状腺滤泡细胞积累放射性碘 (RAI) 的能力。然而，在一部分 NMTC 患者中发生肿瘤去分化，导致 RAI 抗性。地高辛已被证明可以在体外恢复低分化和间变性 NMTC 细胞的碘吸收能力，称为再分化。本研究的目的是调查在体内在TPO-的Cre / LSL-型Braf地高辛影响^V600E小鼠和地高辛处理的NMTC的患者。

方法

患有甲状腺癌的小鼠接受 3D 超声监测肿瘤生长，并接受¹²⁴ I PET/CT 测量肿瘤内碘摄取。对肿瘤组织的死后分析包括基因表达谱和肿瘤内自噬活性的测量。通过 PALGA（荷兰病理学登记处），从 11 名使用地高辛的非间变性 NMTC 患者中获得了存档的肿瘤材料。将这些患者的临床特征和肿瘤材料与 11 名从未接受过地高辛治疗的匹配对照 NMTC 患者进行比较。

结果

我们发现，在小鼠中，短程地高辛治疗后，肿瘤生长受到抑制，¹²⁴ I 积累持续增加。尸检分析显示，与载体治疗的小鼠相比，地高辛治疗增加了小鼠肿瘤中的自噬活性和甲状腺特异性基因的表达。与匹配的对照 NMTC 患者相比，地高辛治疗的 NMTC 患者表现出显着更高的自噬活性和更高的分化状态，并且与良好的临床结果相关。

结论

这些体内数据支持这样一种假设，即地高辛可能代表一种重新定位的辅助治疗方式，可以抑制肿瘤生长并提高 RAI 难治性 NMTC 患者的 RAI 敏感性。