Digoxin Treatment Reactivates in Vivo Radioactive Iodide Uptake and Correlates with Favorable Clinical Outcome in Non-medullary Thyroid Cancer

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2021 Feb 3

PMID 33534128

Citations 5

Authors

Thomas Crezee

Marika H Tesselaar

James Nagarajah

Willem E Corver

Johannes Morreau

Catrin Pritchard

Shioko Kimura

Josephina G Kuiper

Ilse van Engen-van Grunsven

Jan W A Smit

Romana T Netea-Maier

Theo S Plantinga

Affiliations

Soon will be listed here.

Abstract

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 mice and digoxin-treated NMTC patients.

Methods: 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.

Results: 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.

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.

Citing Articles

Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.

van Houten P, Nagarajah J, Walraven J, Jaeger M, van Engen-van Grunsven A, Smit J Eur Thyroid J. 2024; 13(4).

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Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Sayour N, Paal A, Ameri P, Meijers W, Minotti G, Andreadou I Eur Heart J. 2024; 45(14):1224-1240.

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The new insights into autophagy in thyroid cancer progression.

Shi Y, Chen S, Liu R J Transl Med. 2023; 21(1):413.

PMID: 37355631 PMC: 10290383. DOI: 10.1186/s12967-023-04265-6.

Cardiac Glycosides as Autophagy Modulators.

Skubnik J, Pavlickova V, Psotova J, Rimpelova S Cells. 2021; 10(12).

PMID: 34943848 PMC: 8699753. DOI: 10.3390/cells10123341.

Structural Insights into the Interactions of Digoxin and Na/K-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation.

Ren Y, Wu S, Burdette J, Cheng X, Kinghorn A Molecules. 2021; 26(12).

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