Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Goss, Paul E.; Qi, Shangle; Hu, Haijun

doi:10.1016/j.jsbmb.2009.01.005

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…This latter observation is undoubtedly more surprising because numerous clinical observations reported that TAM is able to promote or to worsen fatty liver in women prescribed with this treatment for breast cancer, although recent studies concluded that the incidence of TAM‐induced steatosis is very low . Studies conducted in rodent models led to divergent results depending on the experimental settings, some of them reproducing TAM‐induced steatosis while others, in perfect agreement with our observations, reported protective effects of TAM on the liver but also on glucose and lipid metabolism . Accordingly, Ceasrine et al highlighted the need for caution in the interpretation of metabolic studies that require transient high‐dose TAM administration protocols for creating conditional KO in tamoxifen‐inducible estrogen receptor ( ERT2 ) ‐Cre thyroglobulin ( Tg ) mice, demonstrating an improved glucose tolerance in both male and female mice 1 week after the last dose and even 3 weeks later in male mice.…”

Section: Discussionsupporting

confidence: 81%

“…(20) Studies conducted in rodent models led to divergent results depending on the experimental settings, some of them reproducing TAMinduced steatosis (21,22) while others, in perfect agreement with our observations, reported protective effects of TAM on the liver (23,24) but also on glucose and lipid metabolism. (24)(25)(26)(27)(28) Accordingly, Ceasrine et al (24) highlighted the need for caution in the interpretation of metabolic studies that require transient high-dose TAM administration protocols for creating conditional KO in tamoxifen-inducible estrogen receptor (ERT2)-Cre thyroglobulin (Tg) mice, demonstrating an improved glucose tolerance in both male and female mice 1 week after the last dose and even 3 weeks later in male mice.…”

Section: Discussionmentioning

confidence: 99%

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Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

et al. 2019

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Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17β‐estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte‐specific ERα deletion ( LERKO mice) and their wild‐type (WT) littermates were fed a high‐fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD‐induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM‐mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole‐body protective role for liver‐derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM‐treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD‐fed GDF15‐ knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

et al. 2019

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“…Upon recovery for 2 weeks, the OVX rats were randomly divided into seven treatment groups and orally administrated with vehicle, 17β-estradiol (2 mg/kg day) as positive control, tamoxifen (1 mg/kg day), raloxifene (3 mg/kg day), DBT (3 g/kg day), as well as combinations of DBT and either tamoxifen or raloxifene for 12 consecutive weeks. Dosages of drugs were conversed based on their clinical dosages and previous studies ( Maricic and Gluck, 2002 ; Cooke et al, 2008 ; Ahmet-Camcioglu et al, 2009 ; Goss et al, 2009 ). Dosage of DBT was coverted from its clinical dose: 30 g of AR and 6 g of ASR ( Zierau et al, 2014 ).…”

Section: Methodsmentioning

confidence: 99%

Bone Protective Effects of Danggui Buxue Tang Alone and in Combination With Tamoxifen or Raloxifene in vivo and in vitro

et al. 2018

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Danggui Buxue Tang (DBT), a traditional Chinese Medicine decoction containing Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), is commonly prescribed for women in China as a remedy for menopausal symptoms. Previous study indicated that DBT stimulated cell growth and differentiation of human osteosarcoma MG-63 cells and exhibited estrogenic properties via estrogen receptors (ERs). The present study aimed to study the bone protective effects of DBT and its potential interactions with selective estrogen receptor modulators (SERMs, tamoxifen and raloxifene) in both in vivo and in vitro models as they act via similar ERs. Six-month-old Sprague-Dawley rats were randomly assigned to the following treatments for 12 weeks: (1) sham-operated control group with vehicle (sham), (2) ovariectomized group with vehicle (OVX), (3) OVX with 17β-estradiol (E2, 2.0 mg/kg day), (4) OVX with tamoxifen (Tamo, 1.0 mg/kg day), (5) OVX with raloxifene (Ralo, 3.0 mg/kg day), (6) OVX with DBT (DBT, 3.0 g/kg day), (7) OVX with DBT+Tamoxifen (DBT+Tamo), and (8) OVX with DBT+Raloxifene (DBT+Ralo). Effects of DBT and potential interactions between DBT and SERMs were also evaluated in MG-63 cells. DBT, tamoxifen, raloxifene, and their combinations significantly increased bone mineral density (BMD) and improved trabecular bone properties, including bone surface (BS), trabecular bone number (Tb.N), and trabecular bone separation (Tb.Sp), as well as restored changes in bone turnover biomarkers and mRNA expression of genes involved in bone metabolism in OVX rats. Furthermore, DBT, SERMs, and their combinations significantly increased serum estradiol and suppressed follicle stimulating hormone and luteinizing hormone in OVX rats, suggesting the possible involvement of the hypothalamus–pituitary–gonadal axis in mediating their bone protective effects. However, SERMs, but not DBT, significantly increased uterus index in OVX rats. DBT significantly induced ALP activity and estrogen response element-dependent transcription in MG-63 cells. Our study demonstrated that DBT alone and in combinations with SERMs could exert bone protective effects in vitro and in vivo.

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“…[4][5][6] It is an orally administered triphenylethylene derivative with antiestrogenic activity that is primarily used in the treatment of patients with metastatic breast cancer. [7][8][9][10][11] The radiolabeled compounds of TAM and TAM derivatives specific to the ERs were prepared in numerous studies. Regarding the mechanism of action of the radiolabeled TOR, only 11 C-and 3 H-related studies were performed, to today date.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Novel Antiestrogen Radioligand (^99mTc-TOR-DTPA)

Yurt

Müftüler

Ünak

et al. 2009

Cancer Biotherapy and Radiopharmaceuticals

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This study was aimed at developing a hydrophilic radioligand as an antiestrogen drug derivative to be used for imaging breast tumors. Toremifene [TOR; 4-chloro-1,2-diphenyl-1-(4-(2-(N,N-di-methylamino)ethoxy)phenyl)-1-butene, as citrate salt] was selected as the starting material to be derived, since it has been used extensively as an antiestrogen drug for treatment and prevention of human breast cancer. An antiestrogen drug derivative, TOR attached to diethylenetriamine pentaacetic acid (DTPA), was synthesized by two experimental treatments, including a purification and a reaction step. We described the synthesis of this TOR derivative, (3Z)-4-{4-[2-(dimethylamino) ethoxy] phenyl}-3,4-diphenylbut-3-en-1-ylN,N-bis[2-(2,6-dioxomorpholin-4-yl)ethyl]glycinate (TOR-DTPA), in detail. Mass spectroscopy confirmed the expected structures. TOR-DTPA was labeled with technetium-99m ((99m)Tc), using stannous chloride (SnCl(2)) as the reducing agent. Biodistribution studies were performed on female Albino Wistar rats. Quality controls, radiochemical yield, and stability studies were done utilizing high-performance liquid chromatography, radioelectrophoresis, thin-layer chromatography, and thin-layer radiochromatography methods. The synthesized compound was found to be hydrophilic and anionic, with high stability for the duration of the testing period in vitro. The results indicated that the radiolabeled compound has estrogen-receptor specificity, especially for the breast tissue. It is highly possible that this compound could be used for imaging breast tumors as a novel technetium-labeled hydrophilic estrogen derivative radioligand.

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Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Cited by 6 publications

References 34 publications

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

Bone Protective Effects of Danggui Buxue Tang Alone and in Combination With Tamoxifen or Raloxifene in vivo and in vitro

Synthesis of a Novel Antiestrogen Radioligand (^99mTc-TOR-DTPA)

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Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Cited by 6 publications

References 34 publications

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

Bone Protective Effects of Danggui Buxue Tang Alone and in Combination With Tamoxifen or Raloxifene in vivo and in vitro

Synthesis of a Novel Antiestrogen Radioligand (99mTc-TOR-DTPA)

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Product

Resources

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Synthesis of a Novel Antiestrogen Radioligand (^99mTc-TOR-DTPA)