Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin

Lakshmanan, Aparna; Scarberry, Daniel; Green, Jill A.; Zhang, Xiaoli; Selmi-Ruby, Samia; Jhiang, Sissy

doi:10.18632/oncotarget.5172

Cited by 31 publications

(26 citation statements)

References 48 publications

(60 reference statements)

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“…Our results are consistent with the results of a study by Trovisco et al that enrolled 280 European patients [ 19 ] but conflict with the results of Xing et al, who reported an association of the BRAF V600E mutation with higher mortality among PTC patients [ 4 ]. However, the BRAF V600E mutation plays a role in the lack of avidity of PTCs for radioactive iodine[ 20 ], thus explaining the higher recurrence rate[ 21 ] and increased risk of disease-specific death.…”

Section: Discussionmentioning

confidence: 99%

BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Carcinoma in Chinese Patients

Sun

Zhang

et al. 2016

PLoS ONE

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BackgroundThe BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations have been reported in papillary thyroid carcinoma (PTC). The aim of this retrospective cross-sectional study was to add further information regarding the prevalence of the BRAF V600E and TERT promoter mutations in Chinese PTC and their clinicopathological associations.MethodsWe detected the BRAF V600E mutation and TERT promoter mutations in 455 Chinese PTC patients and analyzed the association of these mutations with several clinicopathological features.ResultsThe BRAF V600E mutation was detected in 343 (75.4%) of 455 cases and was significantly associated with older age (p<0.001) and conventional subtype (p = 0.003). TERT promoter mutations were detected in 19 (4.4%) of 434 PTCs and were associated with older age (p<0.001), larger tumor size (p = 0.024), and advanced TNM stage(p<0.001). Of the 19 patients that were positive for TERT promoter mutations, 18 (94.7%) also harbored the BRAF V600E mutation.ConclusionWe determined the prevalence and clinicopathological associations of BRAF V600E and TERT promoter mutations in Chinese PTC patients. TERT promoter mutations but not the BRAF V600E mutation were associated with more advanced TNM stage upon diagnosis.

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Section: Discussionmentioning

confidence: 99%

BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Carcinoma in Chinese Patients

Sun

Zhang

et al. 2016

PLoS ONE

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“…Though PI3K inhibitors could induce RAIU by diminished iodide efflux rate where TGF-β, a secreted cytokine facilitates the growth of thyroid cancers, has been observed to reverse the effect. A combination treatment of apigenin with PI3K inhibitor GDC-0941 attenuated the effect of TGF-β increasing RAIU in both BRAFV600E and RET/PTC3 expressing cells [197]. …”

Section: 0 Effect Of Apigenin In Various Human Cancersmentioning

confidence: 99%

Plant Flavone Apigenin: an Emerging Anticancer Agent

et al. 2017

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Research in cancer chemoprevention provides convincing evidence that increased intake of vegetables and fruits may reduce the risk of several human malignancies. Phytochemicals present therein provide beneficial anti-inflammatory and antioxidant properties that serve to improve the cellular microenvironment. Compounds known as flavonoids categorized anthocyanidins, flavonols, flavanones, flavonols, flavones, and isoflavones have shown considerable promise as chemopreventive agents. Apigenin (4′, 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties affecting several molecular and cellular targets used to treat various human diseases. Epidemiologic and case-control studies have suggested apigenin reduces the risk of certain cancers. Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers. Apigenin’s anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies. Here we discuss the anticancer role of apigenin highlighting its potential activity as a chemopreventive and therapeutic agent. We also highlight the current caveats that preclude apigenin for its use in the human trials.

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“…This results from multiple mechanisms elicited by several signaling pathways involved in thyroid tumorigenesis [33]. Consistently, most of the DTC-derived cell lines available fail to express thyroid-specific genes, including NIS and the TSH receptor [34], which hampers the study of TSH-mediated regulation on NIS expression in these neoplastic cellular models (S1 Fig). Nevertheless, the study of the mechanisms underlying NIS functional regulation using non-neoplastic, TSH-responsive, thyroid cell models have been shown to allow the identification of key regulatory events that can be further translated into the malignant context [35][36][37][38].…”

Section: Resultsmentioning

confidence: 99%

TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

et al. 2020

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The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up-or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.

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Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin

Cited by 31 publications

References 48 publications

BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Carcinoma in Chinese Patients

BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Carcinoma in Chinese Patients

Plant Flavone Apigenin: an Emerging Anticancer Agent

TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

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