Digoxin treatment reactivates in vivo radioactive iodide uptake and correlates with favorable clinical outcome in non‐medullary thyroid cancer

Crezee, Thomas; Tesselaar, Marika H.; Nagarajah, James; Corver, Willem E.; Morreau, J.; Pritchard, Catrin; Kimura, Shioko; Kuiper, Josephina G.; Grunsven, Ilse van Engen-van; Smit, J.W.A.; Netea‐Maier, Romana T.; Plantinga, Theo S.

doi:10.1007/s13402-021-00588-y

Cited by 8 publications

(4 citation statements)

References 59 publications

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“…Besides binding to its molecular targets, digoxin was also found to mediate its antitumor activity by induction of apoptosis and autophagy [ 36 , 42 , 43 , 44 , 45 ], for which both histone deacetylases (HDACs) and inhibitor of apoptosis (IAP) have been proposed as important targets [ 46 , 47 , 48 ]. There are three classes with more than 10 members in the human HDAC family, with the similarity of the members in the same class being higher than that in different classes; the structures of these proteins are notably similar ( Figure S8 ).…”

Section: Resultsmentioning

confidence: 99%

“…The low binding affinities indicate that digoxin does not induce apoptosis and autophagy in human cancer cells by targeting HDACs or IAPs directly, but it may mediate these activities through the HIF-1α, NKA, and NF-κB signaling pathways [ 36 , 42 , 43 , 44 , 45 ]. However, better binding between digoxigenin and HDACs was observed, which suggests that this aglycone may exhibit potential antitumor activity through induction of the HDAC-mediated autophagy or signaling.…”

Section: Resultsmentioning

confidence: 99%

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

Ren

Burdette

et al. 2021

Molecules

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Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin’s cytotoxicity and interactions with Na+/K+-ATPase. The docking profiles for digoxin and several derivatives and Na+/K+-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na+/K+-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na+/K+-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Ren

Burdette

et al. 2021

Molecules

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“…Digoxin exposure has been noticed to promote autophagy and accelerate iodine accumulation in mice model bearing TC. The tumor volume is shrank after the treatment, thus it is assumed that autophagy is positively correlated to iodide uptake that constrains tumor growth [ 81 ]. This result is also confirmed in other studies.…”

Section: Autophagy Can Be Regulated By Radiotherapy In Tcmentioning

confidence: 99%

The new insights into autophagy in thyroid cancer progression

2023

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In recent decades, the incidence of thyroid cancer keeps growing at a shocking rate, which has aroused increasing concerns worldwide. Autophagy is a fundamental and ubiquitous biological event conserved in mammals including humans. Basically, autophagy is a catabolic process that cellular components including small molecules and damaged organelles are degraded for recycle to meet the energy needs, especially under the extreme conditions. The dysregulated autophagy has indicated to be involved in thyroid cancer progression. The enhancement of autophagy can lead to autophagic cell death during the degradation while the produced energies can be utilized by the rest of the cancerous tissue, thus this influence could be bidirectional, which plays either a tumor-suppressive or oncogenic role. Accordingly, autophagy can be suppressed by therapeutic agents and is thus regarded as a drug target for thyroid cancer treatments. In the present review, a brief description of autophagy and roles of autophagy in tumor context are given. We have addressed summary of the mechanisms and functions of autophagy in thyroid cancer. Some potential autophagy-targeted treatments are also summarized. The aim of the review is linking autophagy to thyroid cancer, so as to develop novel approaches to better control cancer progression.

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“…However, autophagy induction by digoxin, might not always be a big concern in anticancer therapy. A recent study by Crezee et al [ 87 ] shows digoxin as a potential treatment option for non-medullary thyroid cancer (NMTC) patients. In the cohort of patients suffering from NMTC with cell dedifferentiation, the classic therapy with radioactive iodine is not successful, since dedifferentiated cells are not able to accumulate the drug.…”

Section: Cardiac Glycosides As Autophagy Modulatorsmentioning

confidence: 99%

Cardiac Glycosides as Autophagy Modulators

Škubník

Pavlíčková

Psotová

et al. 2021

Cells

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Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.

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Digoxin treatment reactivates in vivo radioactive iodide uptake and correlates with favorable clinical outcome in non‐medullary thyroid cancer

Cited by 8 publications

References 59 publications

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

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

The new insights into autophagy in thyroid cancer progression

Cardiac Glycosides as Autophagy Modulators

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