Department of Pathology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, Nijmegen, 6500 HB, The Netherlands.
Department of Radiology & Nuclear Medicine, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Cell Oncol (Dordr). 2021 Jun;44(3):611-625. doi: 10.1007/s13402-021-00588-y. Epub 2021 Feb 3.
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 mice and digoxin-treated NMTC patients.
Mice with thyroid cancer were subjected to 3D ultrasound for monitoring tumor growth and I 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.
We found that in mice, tumor growth was inhibited and I 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.
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.
非髓样甲状腺癌（NMTC）的治疗基于甲状腺滤泡细胞摄取放射性碘（RAI）的能力。然而，在 NMTC 患者的亚组中，肿瘤去分化发生，导致 RAI 耐药。地高辛已被证明可在体外恢复低分化和间变性 NMTC 细胞的碘摄取能力，称为再分化。本研究旨在研究地高辛在 TPO-Cre/LSL-Braf 小鼠和地高辛治疗的 NMTC 患者中的体内作用。
患有甲状腺癌的小鼠接受 3D 超声监测肿瘤生长和 I PET/CT 测量肿瘤内碘摄取。对肿瘤组织进行的死后分析包括基因表达谱分析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 名从未接受地高辛治疗的匹配 NMTC 患者进行比较。
我们发现，在小鼠中，短期地高辛治疗可抑制肿瘤生长并持续增加 I 积聚。死后分析显示，与接受载体治疗的小鼠相比，地高辛治疗可增加小鼠肿瘤中的自噬活性并增强甲状腺特异性基因的表达。与匹配的 NMTC 患者相比，地高辛治疗的 NMTC 患者表现出明显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。
这些体内数据支持地高辛可能代表一种重新定位的辅助治疗方式的假设，该方式可抑制肿瘤生长并提高 RAI 难治性 NMTC 患者的 RAI 敏感性。
