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Naftali Stern - One of the best experts on this subject based on the ideXlab platform.
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a sorafenib sparing effect in the treatment of thyroid carcinoma cells attained by co treatment with a novel Isoflavone Derivative and 1 25 dihydroxyvitamin d3
The Journal of Steroid Biochemistry and Molecular Biology, 2018Co-Authors: Elena Izkhakov, Fortune Kohen, Naftali Stern, Orli Sharon, Esther Knoll, Asaf Aizic, Dan M Fliss, Dalia SomjenAbstract:Abstract Background Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that Isoflavone Derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). Methods In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERβ, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. Results 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 μg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 μg/ml) alone. Conclusions The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.
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anti proliferative effects of a novel Isoflavone Derivative in medullary thyroid carcinoma an in vitro study
The Journal of Steroid Biochemistry and Molecular Biology, 2012Co-Authors: Yona Greenman, Meital Graficohen, Orly Sharon, Etty Knoll, Fortune Kohen, Naftali Stern, Dalia SomjenAbstract:a b s t r a c t Currently available treatments for patients with medullary thyroid carcinoma (MTC) with residual or recurrent disease after primary surgery have low efficacy rates. In view of the possible role of estrogen in the development of thyroid neoplasia, we explored whether proliferation of the human MTC TT cell line, might be curbed by carboxy-daidzein-tBoc (cD-tBoc), a novel Isoflavone Derivative. Estrogen receptor (ER) mRNA expression in TT cells was more abundant than ER, with a ratio of 48:1. Estradiol-17 (E2) increased DNA synthesis in a dose dependent manner. (3H)-thymidine incorporation was also stim- ulated by the ER agonist DPN and the ER agonist PPT. cD-tBoc inhibited TT cell growth as assessed by thymidine incorporation, XTT assay, and microscopic analysis of culture wells. Creatine kinase spe- cific activity, a marker of the modulatory effects of estrogen on cell energy metabolism, was likewise inhibited. The inhibitory effect of cD-tBoc on ( 3 H)-thymidine incorporation could be blocked by the ER antagonist PTHPP but not by the ER antagonist MPP, suggesting that the antiproliferative effect of cD- tBoc on these cells is mediated through ER. Furthermore, cD-tBoc potently increased apoptosis and cell necrosis. Co-incubation with the antiapoptotic agent Z-VAD-FMK reversed the growth inhibitory effect elicited by cD-tBoc. These results support the hypothesis that estrogens are involved in the proliferation of MTC. The potent anti-proliferative effects mediated by Isoflavone Derivatives in the human MTC cell line TT suggest and that this property may be utilized to design effective anti-neoplastic agents.
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growth inhibition of human thyroid carcinoma and goiter cells in vitro by the Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine
Thyroid, 2012Co-Authors: Dalia Somjen, Meital Graficohen, Fortune Kohen, Gary Weisinger, Elena Izkhakov, Zaki Kraiem, Orli Sharon, Dan M Fliss, Daniel Zikk, Naftali SternAbstract:Background: Estrogens may enhance thyroid cancer cell growth. We have recently reported that a novel Isoflavone-derived anti-estrogenic compound developed in our laboratory, the N-t-boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc), can induce apoptosis and retard growth in human thyroid carcinoma cell lines through inhibitory interaction on estrogen receptor β. Here we tested the hypothesis that cD-tboc can likewise retard cell growth in cultured human thyroid papillary carcinoma cells, normal thyroid cells, and goiter cells removed during thyroidectomy. Methods: In vitro experiments in cultured human thyroid normal, goiter, and papillary thyroid carcinoma (PTC) cells were performed. Estrogen receptors α and β (ERα and ERβ), DNA synthesis and creatine kinase (a marker of estrogenic genomic response), and the effects of cD-tboc on DNA synthesis in cultured human PTC cells were assessed. Results: First, all cell types thus harvested and grown in culture expressed both ERα and ERβ, wi...
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anti thyroid cancer properties of a novel Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine in vitro and in vivo
The Journal of Steroid Biochemistry and Molecular Biology, 2011Co-Authors: Dalia Somjen, Meital Graficohen, Orly Sharon, Fortune Kohen, Sara Katzburg, Gary Weisinger, Elena Izkhakov, Nava Nevo, Zaki Kraiem, Naftali SternAbstract:The incidence of thyroid cancer is up to 3 folds higher in women than in men, suggesting that estrogenic effects may be involved in the pathogenesis of this malignancy. Here, we explore whether or not human thyroid cancer cell growth can be curbed by a novel Isoflavone Derivative generated in our laboratory, the N-t-Boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc). With the exception of the follicular cancer cell line WRO, estrogen receptor (ER)α mRNA was only marginally expressed in cell lines derived from papillary (NPA), follicular (MRO), anaplastic thyroid carcinoma (ARO) such that the expression of estrogen receptor (ER) βmRNA was more abundant than that of ERα mRNA in these cell types. Estradiol-17β (E2; 0.03-300nmol/l) per se increased proliferation in all four cell-types. The ERβ-specific agonist DPN increased [(3)H]-thymidine incorporation in all four thyroid cancer cell lines, whereas the ERα-specific agonist PPT increased growth only in NPA and WRO. By contrast, cD-tboc, derived from the weak estrogen daidzein, did not cause cell growth and dose-dependently diminished cell growth in all four cell lines via apoptosis and not necrosis, as detected by the release of histone-DNA fragments. The cytotoxic growth inhibitory effect of cD-tboc in these cells was modulated by E2 and the general caspase inhibitor Z-VAD-FMK, and the magnitude of this salvage was cell type-and dose-dependent. When nude mice carrying ARO thyroid xenografts were treated with cD-tboc, tumor volume decreased significantly, and no apparent toxicity was observed. These results suggest that cD-tboc may be a promising agent for therapy of thyroid carcinoma either alone or in combination with existing cytotoxic drugs.
Dalia Somjen - One of the best experts on this subject based on the ideXlab platform.
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a sorafenib sparing effect in the treatment of thyroid carcinoma cells attained by co treatment with a novel Isoflavone Derivative and 1 25 dihydroxyvitamin d3
The Journal of Steroid Biochemistry and Molecular Biology, 2018Co-Authors: Elena Izkhakov, Fortune Kohen, Naftali Stern, Orli Sharon, Esther Knoll, Asaf Aizic, Dan M Fliss, Dalia SomjenAbstract:Abstract Background Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that Isoflavone Derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). Methods In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERβ, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. Results 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 μg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 μg/ml) alone. Conclusions The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.
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anti proliferative effects of a novel Isoflavone Derivative in medullary thyroid carcinoma an in vitro study
The Journal of Steroid Biochemistry and Molecular Biology, 2012Co-Authors: Yona Greenman, Meital Graficohen, Orly Sharon, Etty Knoll, Fortune Kohen, Naftali Stern, Dalia SomjenAbstract:a b s t r a c t Currently available treatments for patients with medullary thyroid carcinoma (MTC) with residual or recurrent disease after primary surgery have low efficacy rates. In view of the possible role of estrogen in the development of thyroid neoplasia, we explored whether proliferation of the human MTC TT cell line, might be curbed by carboxy-daidzein-tBoc (cD-tBoc), a novel Isoflavone Derivative. Estrogen receptor (ER) mRNA expression in TT cells was more abundant than ER, with a ratio of 48:1. Estradiol-17 (E2) increased DNA synthesis in a dose dependent manner. (3H)-thymidine incorporation was also stim- ulated by the ER agonist DPN and the ER agonist PPT. cD-tBoc inhibited TT cell growth as assessed by thymidine incorporation, XTT assay, and microscopic analysis of culture wells. Creatine kinase spe- cific activity, a marker of the modulatory effects of estrogen on cell energy metabolism, was likewise inhibited. The inhibitory effect of cD-tBoc on ( 3 H)-thymidine incorporation could be blocked by the ER antagonist PTHPP but not by the ER antagonist MPP, suggesting that the antiproliferative effect of cD- tBoc on these cells is mediated through ER. Furthermore, cD-tBoc potently increased apoptosis and cell necrosis. Co-incubation with the antiapoptotic agent Z-VAD-FMK reversed the growth inhibitory effect elicited by cD-tBoc. These results support the hypothesis that estrogens are involved in the proliferation of MTC. The potent anti-proliferative effects mediated by Isoflavone Derivatives in the human MTC cell line TT suggest and that this property may be utilized to design effective anti-neoplastic agents.
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growth inhibition of human thyroid carcinoma and goiter cells in vitro by the Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine
Thyroid, 2012Co-Authors: Dalia Somjen, Meital Graficohen, Fortune Kohen, Gary Weisinger, Elena Izkhakov, Zaki Kraiem, Orli Sharon, Dan M Fliss, Daniel Zikk, Naftali SternAbstract:Background: Estrogens may enhance thyroid cancer cell growth. We have recently reported that a novel Isoflavone-derived anti-estrogenic compound developed in our laboratory, the N-t-boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc), can induce apoptosis and retard growth in human thyroid carcinoma cell lines through inhibitory interaction on estrogen receptor β. Here we tested the hypothesis that cD-tboc can likewise retard cell growth in cultured human thyroid papillary carcinoma cells, normal thyroid cells, and goiter cells removed during thyroidectomy. Methods: In vitro experiments in cultured human thyroid normal, goiter, and papillary thyroid carcinoma (PTC) cells were performed. Estrogen receptors α and β (ERα and ERβ), DNA synthesis and creatine kinase (a marker of estrogenic genomic response), and the effects of cD-tboc on DNA synthesis in cultured human PTC cells were assessed. Results: First, all cell types thus harvested and grown in culture expressed both ERα and ERβ, wi...
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anti thyroid cancer properties of a novel Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine in vitro and in vivo
The Journal of Steroid Biochemistry and Molecular Biology, 2011Co-Authors: Dalia Somjen, Meital Graficohen, Orly Sharon, Fortune Kohen, Sara Katzburg, Gary Weisinger, Elena Izkhakov, Nava Nevo, Zaki Kraiem, Naftali SternAbstract:The incidence of thyroid cancer is up to 3 folds higher in women than in men, suggesting that estrogenic effects may be involved in the pathogenesis of this malignancy. Here, we explore whether or not human thyroid cancer cell growth can be curbed by a novel Isoflavone Derivative generated in our laboratory, the N-t-Boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc). With the exception of the follicular cancer cell line WRO, estrogen receptor (ER)α mRNA was only marginally expressed in cell lines derived from papillary (NPA), follicular (MRO), anaplastic thyroid carcinoma (ARO) such that the expression of estrogen receptor (ER) βmRNA was more abundant than that of ERα mRNA in these cell types. Estradiol-17β (E2; 0.03-300nmol/l) per se increased proliferation in all four cell-types. The ERβ-specific agonist DPN increased [(3)H]-thymidine incorporation in all four thyroid cancer cell lines, whereas the ERα-specific agonist PPT increased growth only in NPA and WRO. By contrast, cD-tboc, derived from the weak estrogen daidzein, did not cause cell growth and dose-dependently diminished cell growth in all four cell lines via apoptosis and not necrosis, as detected by the release of histone-DNA fragments. The cytotoxic growth inhibitory effect of cD-tboc in these cells was modulated by E2 and the general caspase inhibitor Z-VAD-FMK, and the magnitude of this salvage was cell type-and dose-dependent. When nude mice carrying ARO thyroid xenografts were treated with cD-tboc, tumor volume decreased significantly, and no apparent toxicity was observed. These results suggest that cD-tboc may be a promising agent for therapy of thyroid carcinoma either alone or in combination with existing cytotoxic drugs.
Jeanyves Reginster - One of the best experts on this subject based on the ideXlab platform.
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effects of ipriflavone and its metabolites on human articular chondrocytes cultivated in clusters
Osteoarthritis and Cartilage, 1996Co-Authors: C Bassleer, Jeanyves Reginster, P Franchimont, Yves Henrotin, Nathalie Franchimont, Vincent GeenenAbstract:Summary Ipriflavone (IP) is an Isoflavone Derivative that was suggested to have bone-sparing effects in post-menopausal and senile osteoporosis. A moderate stimulatory effect of IP and its metabolites on proliferation of osteoblastic cells was reported in rat osteoblastic osteosarcoma cell line. We investigated the effects of different concentrations (0, 1, 10 and 100 μ g/ml) of IP and its metabolites (MET I, II, III and V) on the incorporation of [ 3 H]thymidine and production of proteoglycans (PG) and type II collagen (COL II) by human articular chondrocytes during a 12-day period, in a three-dimensional chondrocyte culture model. [ 3 H]thymidine uptake was measured in chondrocyte clusters, and specific PG and COL II radioimmunoassays were performed every 4 days on the culture medium and cell clusters. Incubation with IP or its metabolites did not affect [ 3 H]thymidine uptake regardless of the dose. PG released into the culture medium and PG cluster content rose significantly ( P μ g/ml). MET I increased PG release in culture medium (10 and 100 μ g/ml) and PG cluster content (100 μ g/ml). MET II has no effect on PG production. MET III increased PG in culture medium (100 μ g/ml) but did not influence PG cluster content while MET V (100 μ g/ml) increased both PG release in culture medium and PG cluster content. COL II release in culture medium and COL II cluster content were significantly ( P μ g/ml), MET III (1, 10 and 100 μ g/ml) or MET V (100 μ g/ml). MET I and II did not significantly affect COL II production.
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ipriflavone pharmacological properties and usefulness in postmenopausal osteoporosis
Bone and Mineral, 1993Co-Authors: Jeanyves ReginsterAbstract:Ipriflavone (IP) is an Isoflavone Derivative available in several countries for investigational and/or therapeutic use. Inhibition of bone resorption was demonstrated in several models, both in vitro and in vivo for IP and its metabolites. Their mechanisms of action on bone are not yet fully elucidated but some of them are widely accepted. IP does not possess, per se, any estrogenic activity. It appears that IP-related inhibition of bone resorption might be mediated by an indirect effect on osteoclast and related to an inhibition of recruitment and/or differentiation of pre-osteoclast, maybe through a modulation of osteoblast response to PTH. Clinical studies in Paget's disease of bone or primary hyperparathyroidism have confirmed preferential inhibition of bone resorption suggesting a clinical interest in postmenopausal osteoporosis. Preliminary (1 year) results of double blind placebo controlled studies designed in postmenopausal and senile osteoporosis confirm a reduction in bone turnover rate in patients treated with 600 mg/day of IP, resulting in a significant bone-sparing effect both at lumbar and radial levels. All clinical and pharmacological trials confirm a very good tolerance of IP with a frequency of adverse reactions equal to that observed during administration of a placebo. Providing ongoing studies will confirm the actual promising preliminary results, IP seems a very interesting new non hormonal approach for prevention and treatment of postmenopausal and senile osteoporosis.
Fortune Kohen - One of the best experts on this subject based on the ideXlab platform.
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a sorafenib sparing effect in the treatment of thyroid carcinoma cells attained by co treatment with a novel Isoflavone Derivative and 1 25 dihydroxyvitamin d3
The Journal of Steroid Biochemistry and Molecular Biology, 2018Co-Authors: Elena Izkhakov, Fortune Kohen, Naftali Stern, Orli Sharon, Esther Knoll, Asaf Aizic, Dan M Fliss, Dalia SomjenAbstract:Abstract Background Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that Isoflavone Derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). Methods In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERβ, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. Results 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 μg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 μg/ml) alone. Conclusions The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.
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anti proliferative effects of a novel Isoflavone Derivative in medullary thyroid carcinoma an in vitro study
The Journal of Steroid Biochemistry and Molecular Biology, 2012Co-Authors: Yona Greenman, Meital Graficohen, Orly Sharon, Etty Knoll, Fortune Kohen, Naftali Stern, Dalia SomjenAbstract:a b s t r a c t Currently available treatments for patients with medullary thyroid carcinoma (MTC) with residual or recurrent disease after primary surgery have low efficacy rates. In view of the possible role of estrogen in the development of thyroid neoplasia, we explored whether proliferation of the human MTC TT cell line, might be curbed by carboxy-daidzein-tBoc (cD-tBoc), a novel Isoflavone Derivative. Estrogen receptor (ER) mRNA expression in TT cells was more abundant than ER, with a ratio of 48:1. Estradiol-17 (E2) increased DNA synthesis in a dose dependent manner. (3H)-thymidine incorporation was also stim- ulated by the ER agonist DPN and the ER agonist PPT. cD-tBoc inhibited TT cell growth as assessed by thymidine incorporation, XTT assay, and microscopic analysis of culture wells. Creatine kinase spe- cific activity, a marker of the modulatory effects of estrogen on cell energy metabolism, was likewise inhibited. The inhibitory effect of cD-tBoc on ( 3 H)-thymidine incorporation could be blocked by the ER antagonist PTHPP but not by the ER antagonist MPP, suggesting that the antiproliferative effect of cD- tBoc on these cells is mediated through ER. Furthermore, cD-tBoc potently increased apoptosis and cell necrosis. Co-incubation with the antiapoptotic agent Z-VAD-FMK reversed the growth inhibitory effect elicited by cD-tBoc. These results support the hypothesis that estrogens are involved in the proliferation of MTC. The potent anti-proliferative effects mediated by Isoflavone Derivatives in the human MTC cell line TT suggest and that this property may be utilized to design effective anti-neoplastic agents.
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growth inhibition of human thyroid carcinoma and goiter cells in vitro by the Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine
Thyroid, 2012Co-Authors: Dalia Somjen, Meital Graficohen, Fortune Kohen, Gary Weisinger, Elena Izkhakov, Zaki Kraiem, Orli Sharon, Dan M Fliss, Daniel Zikk, Naftali SternAbstract:Background: Estrogens may enhance thyroid cancer cell growth. We have recently reported that a novel Isoflavone-derived anti-estrogenic compound developed in our laboratory, the N-t-boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc), can induce apoptosis and retard growth in human thyroid carcinoma cell lines through inhibitory interaction on estrogen receptor β. Here we tested the hypothesis that cD-tboc can likewise retard cell growth in cultured human thyroid papillary carcinoma cells, normal thyroid cells, and goiter cells removed during thyroidectomy. Methods: In vitro experiments in cultured human thyroid normal, goiter, and papillary thyroid carcinoma (PTC) cells were performed. Estrogen receptors α and β (ERα and ERβ), DNA synthesis and creatine kinase (a marker of estrogenic genomic response), and the effects of cD-tboc on DNA synthesis in cultured human PTC cells were assessed. Results: First, all cell types thus harvested and grown in culture expressed both ERα and ERβ, wi...
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anti thyroid cancer properties of a novel Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine in vitro and in vivo
The Journal of Steroid Biochemistry and Molecular Biology, 2011Co-Authors: Dalia Somjen, Meital Graficohen, Orly Sharon, Fortune Kohen, Sara Katzburg, Gary Weisinger, Elena Izkhakov, Nava Nevo, Zaki Kraiem, Naftali SternAbstract:The incidence of thyroid cancer is up to 3 folds higher in women than in men, suggesting that estrogenic effects may be involved in the pathogenesis of this malignancy. Here, we explore whether or not human thyroid cancer cell growth can be curbed by a novel Isoflavone Derivative generated in our laboratory, the N-t-Boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc). With the exception of the follicular cancer cell line WRO, estrogen receptor (ER)α mRNA was only marginally expressed in cell lines derived from papillary (NPA), follicular (MRO), anaplastic thyroid carcinoma (ARO) such that the expression of estrogen receptor (ER) βmRNA was more abundant than that of ERα mRNA in these cell types. Estradiol-17β (E2; 0.03-300nmol/l) per se increased proliferation in all four cell-types. The ERβ-specific agonist DPN increased [(3)H]-thymidine incorporation in all four thyroid cancer cell lines, whereas the ERα-specific agonist PPT increased growth only in NPA and WRO. By contrast, cD-tboc, derived from the weak estrogen daidzein, did not cause cell growth and dose-dependently diminished cell growth in all four cell lines via apoptosis and not necrosis, as detected by the release of histone-DNA fragments. The cytotoxic growth inhibitory effect of cD-tboc in these cells was modulated by E2 and the general caspase inhibitor Z-VAD-FMK, and the magnitude of this salvage was cell type-and dose-dependent. When nude mice carrying ARO thyroid xenografts were treated with cD-tboc, tumor volume decreased significantly, and no apparent toxicity was observed. These results suggest that cD-tboc may be a promising agent for therapy of thyroid carcinoma either alone or in combination with existing cytotoxic drugs.
Elena Izkhakov - One of the best experts on this subject based on the ideXlab platform.
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a sorafenib sparing effect in the treatment of thyroid carcinoma cells attained by co treatment with a novel Isoflavone Derivative and 1 25 dihydroxyvitamin d3
The Journal of Steroid Biochemistry and Molecular Biology, 2018Co-Authors: Elena Izkhakov, Fortune Kohen, Naftali Stern, Orli Sharon, Esther Knoll, Asaf Aizic, Dan M Fliss, Dalia SomjenAbstract:Abstract Background Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that Isoflavone Derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). Methods In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERβ, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. Results 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 μg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 μg/ml) alone. Conclusions The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.
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growth inhibition of human thyroid carcinoma and goiter cells in vitro by the Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine
Thyroid, 2012Co-Authors: Dalia Somjen, Meital Graficohen, Fortune Kohen, Gary Weisinger, Elena Izkhakov, Zaki Kraiem, Orli Sharon, Dan M Fliss, Daniel Zikk, Naftali SternAbstract:Background: Estrogens may enhance thyroid cancer cell growth. We have recently reported that a novel Isoflavone-derived anti-estrogenic compound developed in our laboratory, the N-t-boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc), can induce apoptosis and retard growth in human thyroid carcinoma cell lines through inhibitory interaction on estrogen receptor β. Here we tested the hypothesis that cD-tboc can likewise retard cell growth in cultured human thyroid papillary carcinoma cells, normal thyroid cells, and goiter cells removed during thyroidectomy. Methods: In vitro experiments in cultured human thyroid normal, goiter, and papillary thyroid carcinoma (PTC) cells were performed. Estrogen receptors α and β (ERα and ERβ), DNA synthesis and creatine kinase (a marker of estrogenic genomic response), and the effects of cD-tboc on DNA synthesis in cultured human PTC cells were assessed. Results: First, all cell types thus harvested and grown in culture expressed both ERα and ERβ, wi...
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anti thyroid cancer properties of a novel Isoflavone Derivative 7 o carboxymethyl daidzein conjugated to n t boc hexylenediamine in vitro and in vivo
The Journal of Steroid Biochemistry and Molecular Biology, 2011Co-Authors: Dalia Somjen, Meital Graficohen, Orly Sharon, Fortune Kohen, Sara Katzburg, Gary Weisinger, Elena Izkhakov, Nava Nevo, Zaki Kraiem, Naftali SternAbstract:The incidence of thyroid cancer is up to 3 folds higher in women than in men, suggesting that estrogenic effects may be involved in the pathogenesis of this malignancy. Here, we explore whether or not human thyroid cancer cell growth can be curbed by a novel Isoflavone Derivative generated in our laboratory, the N-t-Boc-hexylenediamine Derivative of 7-(O)-carboxymethyl daidzein (cD-tboc). With the exception of the follicular cancer cell line WRO, estrogen receptor (ER)α mRNA was only marginally expressed in cell lines derived from papillary (NPA), follicular (MRO), anaplastic thyroid carcinoma (ARO) such that the expression of estrogen receptor (ER) βmRNA was more abundant than that of ERα mRNA in these cell types. Estradiol-17β (E2; 0.03-300nmol/l) per se increased proliferation in all four cell-types. The ERβ-specific agonist DPN increased [(3)H]-thymidine incorporation in all four thyroid cancer cell lines, whereas the ERα-specific agonist PPT increased growth only in NPA and WRO. By contrast, cD-tboc, derived from the weak estrogen daidzein, did not cause cell growth and dose-dependently diminished cell growth in all four cell lines via apoptosis and not necrosis, as detected by the release of histone-DNA fragments. The cytotoxic growth inhibitory effect of cD-tboc in these cells was modulated by E2 and the general caspase inhibitor Z-VAD-FMK, and the magnitude of this salvage was cell type-and dose-dependent. When nude mice carrying ARO thyroid xenografts were treated with cD-tboc, tumor volume decreased significantly, and no apparent toxicity was observed. These results suggest that cD-tboc may be a promising agent for therapy of thyroid carcinoma either alone or in combination with existing cytotoxic drugs.
