Digoxin treatment is associated with thyroid cancer differentiation and radioactive iodide treatment response
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PROVIDER: PRJNA445240 | ENA |
REPOSITORIES: ENA
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Project description:Non-medullary thyroid cancer (NMTC) is the most frequent endocrine tumor with in most cases a good prognosis. Unfortunately, 30-40% of patients with metastatic NMTC are unresponsive to 131-I radioactive iodide (RAI) treatment as a result of tumor dedifferentiation. Autophagy has emerged as an important mechanism involved in NMTC dedifferentiation. Furthermore, activation of autophagy by cardiac glycosides such as digoxin has been demonstrated to induce effective in vitro redifferentiation of poorly differentiated and anaplastic thyroid cancer cell lines, thereby restoring sensitivity to RAI treatment. However, the in vivo effects of digoxin treatment on tumor differentiation in NMTC patients remains unclear. In the present retrospective clinical study, archived tumor material obtained from NMTC patients that received digoxin as treatment of heart disease before and after NMTC diagnosis was investigated. By a national PALGA-PHARMO database search, 11 digoxin-treated NMTC patients were included encompassing all major histological NMTC subtypes. In addition, 11 control NMTC patients never treated with digoxin were included that were matched for age, gender, histological tumor type, TNM staging and genetic profile. From the collected tumor material, autophagy activity has been determined by LC3 immunofluorescent staining and RNA expression profiles have been generated by RNA sequencing to assess differential expression of thyroid-specific genes. Interestingly, the results indicate that tumor material from digoxin-treated NMTC patients exhibit significantly higher autophagy activity as compared to tumor material of matched control NMTC patients. Moreover, in all 11 tumor tissues obtained from digoxin-treated NTMC patients the differentiation status was profoundly higher as compared to the matched control NMTC patients, of which the effect size was however dependent on histological NMTC subtypes and genetic profile of the tumor. In conclusion, treatment of NMTC with digoxin before and after NMTC diagnosis is associated with a higher tumor differentiation grade as compared to tumor tissue from closely matched NMTC patients not treated with digoxin. These in vivo data confirm our previous in vitro findings and provide accumulating evidence that digoxin could represent a beneficial adjunctive treatment modality to improve RAI sensitivity in patients with RAI-refractory thyroid carcinoma.
2020-10-01 | GSE112202 | GEO
Project description:Efficacy of a selective MEK (trametinib) and BRAFV600E (dabrafenib) inhibitors associated with radioactive iodine (RAI) for the treatment of refractory metastatic differentiated thyroid cancer with RAS or BRAFV600E mutation. To evaluate the objective response rate according to RECIST criteria in thyroid cancer patients with metastatic radioactive iodine (RAI) refractory disease, 6 months after a treatment combining in each arm of the phase II trial (patients with RAS mutation or patients with BRAFV600E mutation): - Arm A: 6 weeks of trametinib followed by RAI treatment (5.5 GBq following rhTSH) in patients with RAS mutation - Arm B: 6 weeks of trametinib plus dabrafenib followed by RAI treatment (5.5 GBq following rhTSH) in patients with BRAFV600E mutation
2023-09-01 | E-MTAB-12837 | biostudies-arrayexpress
Project description:Efficacy of a selective MEK (trametinib) and BRAFV600E (dabrafenib) inhibitors associated with radioactive iodine (RAI) for the treatment of refractory metastatic differentiated thyroid cancer with RAS (current cohort) or BRAFV600E mutation. To evaluate the objective response rate according to RECIST criteria in thyroid cancer patients with metastatic radioactive iodine (RAI) refractory disease, 6 months after a treatment combining in each arm of the phase II trial (patients with RAS mutation or patients with BRAFV600E mutation): - Arm A: 6 weeks of trametinib followed by RAI treatment (5.5 GBq following rhTSH) in patients with RAS mutation - Arm B: 6 weeks of trametinib plus dabrafenib followed by RAI treatment (5.5 GBq following rhTSH) in patients with BRAFV600E mutation
2023-09-01 | E-MTAB-12900 | biostudies-arrayexpress
Project description:We report the effect of FDA approved digoxin treatment (50nM for 48h) on the gene expression and alternative splices in control human pluripotent stem cells derived mesenchymal stem cells. Our results demonstrate the effect of digoxin treatment on alternative splice as 258 skipping exons were identified after digoxin treatment. Concerning the gene expression, our results also highlight on the large effect of digoxin treatment on the modulation of gene expression.
2017-06-13 | GSE99944 | GEO
Project description:RNA-seq data of Group 3 and 4 medulloblastoma with digoxin treatment.
2018-10-30 | GSE115542 | GEO
Project description:The inhibitory effect of supra physiological iodide concentrations on thyroid hormone synthesis (Wolff-Chaikoff effect) and thyrocyte proliferation is largely know as iodine autoregulation. However, the molecular mechanisms by which iodide excess modulate thyroid functions remains unclear. In this work, we analyzed the rat follicular cell PCCl3 transcriptome profile under untreated and treated conditions with 10-3M sodium iodide (Na/I). Serial Analysis of Gene Expression revealed several transcripts differentially expressed in response to the iodide showing that excess iodide affects almost all aspects of thyroid cell function and differentiation acting on the iodine autoregulatory mechanism through a complex process. Keywords: comparative genomic analysis
2007-11-02 | GSE7174 | GEO
Project description:A Microarray Search for Effects of Thyrotropin and Iodide on Angiogenesis Factors Objective: Excess iodide has been administered to hyperthyroid patients before thyroid surgery to reduce intraoperative bleeding and oozing. The purpose of this study was to elucidate the mechanism by which iodide reduces blood flow in the hypervascular thyroid gland. Design: Human thyroid follicles were cultured in the presence or absence of thyrotropin (TSH), or in medium containing various concentrations of iodide, and TSH- or iodide-regulated gene expression was analyzed by cDNA microarray. Main outcome: TSH stimulated the expression of thyroglobulin, peroxidase, sodium-iodide symporter, vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PGF) but decreased that of VEGF-C by half. When thyroid follicles were cultured in high-iodide (10-5M) medium, TSH-induced expression of VEGF-A, VEGF-B and PGF was decreased, accompanied by a reduction of VEGF-A release into the medium. Furthermore, expression of putative angiogenesis inhibitors such as urokinase-type plasminogen activator (PLAU) was increased. These findings were confirmed by real-time polymerase chain reaction (PCR) and Northern blot hybridization. Conclusions: We have demonstrated for the first time that iodide at high concentration decreases the expression of the angiogenic factors VEGF-A, VEGF-B, and PGF, accompanied by an increase in the expression of possible anti-angiogenic factors such as PLAU. These proangiogenic and antiangiogenic factors may at least partly account for the iodide-induced decrease in thyroid blood flow.
2008-08-01 | GSE12244 | GEO
Project description:CD4+ T helper lymphocytes that express interleukin-17 (Th17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in Th17 cell differentiation and function with susceptibility to Crohn’s disease, rheumatoid arthritis, and psoriasis1-3. Thus, the pathway towards differentiation of Th17 cells and, perhaps, of related innate lymphoid cells with similar effector functions4, 5, is an attractive target for therapeutic applications. Mouse and human Th17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt, which is required for induction of IL-17 transcription and for the manifestation of Th17-dependent autoimmune disease in mice6. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORγt transcriptional activity. Digoxin inhibited murine Th17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives, 20,22-dihydrodigoxin-21,23-diol (Dig(dhd)) and digoxin-21-salicylidene (Dig(sal)), specifically inhibited induction of IL-17 in human CD4+ T cells. Using these small molecule compounds, we demonstrated that RORγt is imporant for the maintenance of IL-17 expression in mouse and human effector T cells. These data suggest that derivatives of digoxin can be used as chemical probes for development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease. We performed gene expression profiling with total RNA samples isolated from DMSO- or digoxin-treated wildtype or RORγt-deficient cells cultured in Th17 conditions. Total RNA was extracted with TRIzol. RNA was labeled and hybridized to GeneChip Mouse Genome 430 2.0 arrays following the Affymetrix protocols. Data were analyzed in GeneSpring GX11.5.
2011-03-28 | E-GEOD-27241 | biostudies-arrayexpress
Project description:The inhibitory effect of supra physiological iodide concentrations on thyroid hormone synthesis (Wolff-Chaikoff effect) and thyrocyte proliferation is largely know as iodine autoregulation. However, the molecular mechanisms by which iodide excess modulate thyroid functions remains unclear. In this work, we analyzed the rat follicular cell PCCl3 transcriptome profile under untreated and treated conditions with 10-3M sodium iodide (Na/I). Serial Analysis of Gene Expression revealed several transcripts differentially expressed in response to the iodide showing that excess iodide affects almost all aspects of thyroid cell function and differentiation acting on the iodine autoregulatory mechanism through a complex process. Keywords: comparative genomic analysis PCCl3 cells were cultured under untreated and treated conditions with 10-3M NaI during 24 hours
2007-11-01 | E-GEOD-7174 | biostudies-arrayexpress
Project description:We are going to submit a paper entitled “Iodide-induced Chemokines and Genes Related to Immunological Function in Cultured Human Thyroid Follicles” to THYROID
2009-07-14 | GSE16957 | GEO