Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer

Shinderman-Maman, Elena; Cohen, Keren; Moskovich, Dotan; Hercbergs, Aleck; Werner, Haim; Davis, Paul J.; Ellis, Martin; Ashur‐Fabian, Osnat

doi:10.1038/s41598-017-16593-x

Cited by 25 publications

(19 citation statements)

References 58 publications

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“…3-T 1 AM is a potential therapeutic agent for suppressing UM expansion as already indicated in other studies demonstrating that this thyroid hormone metabolite reduces cancer cell growth and viability (Rogowski et al, 2017 ; Shinderman-Maman et al, 2017 ). In UM cells, modulation of their metastatic activity appears to include changes in TRPV1 activity induced by TRPM8 and possibly CB1.…”

Section: Discussionmentioning

confidence: 78%

TRPM8 Activation via 3-Iodothyronamine Blunts VEGF-Induced Transactivation of TRPV1 in Human Uveal Melanoma Cells

et al. 2018

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In human uveal melanoma (UM), tumor enlargement is associated with increases in aqueous humor vascular endothelial growth factor-A (VEGF-A) content that induce neovascularization. 3-Iodothyronamine (3-T1AM), an endogenous thyroid hormone metabolite, activates TRP melastatin 8 (TRPM8), which blunts TRP vanilloid 1 (TRPV1) activation by capsaicin (CAP) in human corneal, conjunctival epithelial cells, and stromal cells. We compare here the effects of TRPM8 activation on VEGF-induced transactivation of TRPV1 in an UM cell line (92.1) with those in normal primary porcine melanocytes (PM) since TRPM8 is upregulated in melanoma. Fluorescence Ca2+-imaging and planar patch-clamping characterized functional channel activities. CAP (20 μM) induced Ca2+ transients and increased whole-cell currents in both the UM cell line and PM whereas TRPM8 agonists, 100 μM menthol and 20 μM icilin, blunted such responses in the UM cells. VEGF (10 ng/ml) elicited Ca2+ transients and augmented whole-cell currents, which were blocked by capsazepine (CPZ; 20 μM) but not by a highly selective TRPM8 blocker, AMTB (20 μM). The VEGF-induced current increases were not augmented by CAP. Both 3-T1AM (1 μM) and menthol (100 μM) increased the whole-cell currents, whereas 20 μM AMTB blocked them. 3-T1AM exposure suppressed both VEGF-induced Ca2+ transients and increases in underlying whole-cell currents. Taken together, functional TRPM8 upregulation in UM 92.1 cells suggests that TRPM8 is a potential drug target for suppressing VEGF induced increases in neovascularization and UM tumor growth since TRPM8 activation blocked VEGF transactivation of TRPV1.

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Section: Discussionmentioning

confidence: 78%

TRPM8 Activation via 3-Iodothyronamine Blunts VEGF-Induced Transactivation of TRPV1 in Human Uveal Melanoma Cells

et al. 2018

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“…The three antagonists, tetraiodoacetic acid (tetrac), triiodothyroacetic acid (triac) and 3-iodothyronamine (T1AM) inhibited cell proliferation and induced cell death and DNA damage in the two ovarian cancer cell lines (OVCAR3 and A2780). Therefore, they concluded that the cytotoxic potential of thyroid hormone derivatives, tetrac, triac and T1AM, in ovarian cancer might provide a much-needed novel therapeutic approach (Shinderman-Maman et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Ditsch

Heublein

Jeschke

et al. 2020

J Cancer Res Clin Oncol

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Purpose Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Among all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Depending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.

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“…Differently from metabolism-related diseases, much less is known about the effects of T1AM on liver carcinogenesis and neoplastic hepatocytes. Only few papers have investigated the effect of T1AM on cancer cells ( 113 , 114 ). In a recent paper it was found that micromolar doses of T1AM and its structural analog SG-2, are able to reduce viability and growth rate of the liver cancer cell line HepG2 and the breast cell line MCF7 ( 114 ) The exact mechanism by which T1AM altered cell viability and growth rate of these cancer cells is not entirely clear.…”

Section: T1am and Liver Cancermentioning

confidence: 99%

Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease

2018

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The signaling pathways activated by thyroid hormone receptors (THR) are of fundamental importance for organogenesis, growth and differentiation, and significantly influence energy metabolism, lipid utilization and glucose homeostasis. Pharmacological control of these pathways would likely impact the treatment of several human diseases characterized by altered metabolism, growth or differentiation. Not surprisingly, biomedical research has been trying for the past decades to pharmacologically target the 3,5,3′-triiodothyronine (T3)/THR axis. In vitro and in vivo studies have provided evidence of the potential utility of the activation of the T3-dependent pathways in metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and in the treatment of hepatocellular carcinoma (HCC). Unfortunately, supra-physiological doses of the THR agonist T3 cause severe thyrotoxicosis thus hampering its therapeutic use. However, the observation that most of the desired beneficial effects of T3 are mediated by the activation of the beta isoform of THR (THRβ) in metabolically active organs has led to the synthesis of a number of THRβ-selective thyromimetics. Among these drugs, GC-1, GC-24, KB141, KB2115, and MB07344 displayed a promising therapeutic strategy for liver diseases. However, although these drugs exhibited encouraging results when tested in the treatment of experimentally-induced obesity, dyslipidemia, and HCC, significant adverse effects limited their use in clinical trials. More recently, evidence has been provided that some metabolites of thyroid hormones (TH), mono and diiodothyronines, could also play a role in the treatment of liver disease. These molecules, for a long time considered inactive byproducts of the metabolism of thyroid hormones, have now been proposed to be able to modulate and control lipid and cell energy metabolism. In this review, we will summarize the current knowledge regarding T3, its metabolites and analogs with reference to their possible clinical application in the treatment of liver disease. In particular, we will focus our attention on NAFLD, non-alcoholic steatohepatitis (NASH) and HCC. In addition, the possible therapeutic use of mono- and diiodothyronines in metabolic and/or neoplastic liver disease will be discussed.

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Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer

Cited by 25 publications

References 58 publications

TRPM8 Activation via 3-Iodothyronamine Blunts VEGF-Induced Transactivation of TRPV1 in Human Uveal Melanoma Cells

TRPM8 Activation via 3-Iodothyronamine Blunts VEGF-Induced Transactivation of TRPV1 in Human Uveal Melanoma Cells

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease

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