Idoxifene (CB7432)
(Synonyms: 艾多昔芬; CB7432) 目录号 : GC33402
Idoxifene (CB7432) (CB7432) 是一种新型的组织特异性选择性雌激素受体调节剂 (SERM)。
Cas No.:116057-75-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | DNA synthesis in cultured HSCs is measured using a Cell Proliferation Biotrack ELISA system. HSCs are cultured in DMEM supplemented with 10% FBS in 96-well plate for 4 d. In the period, the medium is replaced every other day. After 4 d, the culture medium is removed and the same medium with or without 1, 10, or 100 nM of Idoxifene is added to the cells respectively. After the cells are cultured for an additional 24 h, bromodeoxyuridine (BrdU) is added into each well at a final concentration of 10 μM and the cells are incubated with BrdU for 24 h. The incorporated BrdU is detected[1]. |
Animal experiment: | Rats[2]Adult male Wistar rats weighing about 200 g are used for the DMN model of hepatic fibrosis. The animals (n=6 in each group), which comprise groups 2 through 6 are administered a single intraperitoneal injection of 40 mg/kg DMN, diluted with saline. The controls in group 1 (n=6) receive a single dose of saline. The rats in groups 4, 5, and 6 receive daily oral gavage of Idoxifene, in a dosing vehicle (1% methylcellulose) of 10 mL/kg at a dose of 0.02, 0.1, and 0.5 mg/kg/day, respectively, for 14 days after a single injection of DMN. Idoxifene is dissolved in vehicle at a dose of 10 mg/mL as a stock solution. The animals in group 3 receive intraperitoneal injections of Estradiol valerate in olive oil at a dose of 0.5 mg/kg/day, for 14 days after the DMN injection. The animals in group 2 receive vehicle only. Animals are anesthetized with 40 mg/kg sodium pentobarbital either 0, 3, 9, or 14 days after DMN injection, and sacrificed. Blood samples are drawn from the inferior vena cava for analyses of serum levels of E2 and lactate dehydrogenase (LDH), a biomarker for necrosis, and liver tissue specimens are taken for light microscopy and immunohistochemistry. |
References: [1]. Zhou YJ, et al. Inhibitory effects of idoxifene on hepatic fibrosis in rats. Acta Pharmacol Sin. 2005 May;26(5):581-6. | |
Idoxifene (CB7432) is a novel tissue-specific selective estrogen receptor modulator (SERM).
Idoxifene possesses the protective roles in vascular smooth muscle cells by its blunting the angiotensin II-induced production of reactive oxygen species (ROS). Idoxifene evidently suppresses HSC activation, inhibits culture-activated HSC proliferation in a dose-dependent manner, and induces culture-activated HSC apoptosis in a time-dependent manner[1]. Idoxifene acts in bone as an estrogen agonist for osteoblasts, and shows negligible agonist activity in human endometrial cells. Idoxifene and E2 protect hepatocytes from inflammatory cell injury by inhibiting activation of the NF-κB proinflammatory transcription factor[2].
Animals receive daily intraperitoneal injections of Estradiol (0.5 mg/kg) and an oral gavage of Idoxifene (0.02, 0.1, and 0.5 mg/kg) for 3 days after Dimethylnitrosamine (DMN) treatment. The blood levels of LDH and Estradiol (E2) and histological grades (scores 0 to 5) of liver zone 3 necrosis are evaluated. Idoxifene at doses of over 0.1 mg/kg significantly reduces the hepatic levels of collagen and MDA in the DMN model in a dose-dependent manner. Although Idoxifene and E2 are administered by different routes, i.e., by oral ingestion and intraperitoneal injection, respectively, the antifibrotic effect of a dose of 0.5 mg/kg of Idoxifene is somewhat greater than that of the same dose of E2[2].
[1]. Zhou YJ, et al. Inhibitory effects of idoxifene on hepatic fibrosis in rats. Acta Pharmacol Sin. 2005 May;26(5):581-6. [2]. Lu G, et al. Antioxidant and antiapoptotic activities of idoxifene and estradiol in hepatic fibrosis in rats. Life Sci. 2004 Jan 2;74(7):897-907.
| Cas No. | 116057-75-1 | SDF | |
| 别名 | 艾多昔芬; CB7432 | ||
| Canonical SMILES | CC/C(C1=CC=CC=C1)=C(C2=CC=C(OCCN3CCCC3)C=C2)\C4=CC=C(I)C=C4 | ||
| 分子式 | C28H30INO | 分子量 | 523.45 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9104 mL | 9.552 mL | 19.104 mL |
| 5 mM | 0.3821 mL | 1.9104 mL | 3.8208 mL |
| 10 mM | 0.191 mL | 0.9552 mL | 1.9104 mL |
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Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats
Endocrinology 1998 Dec;139(12):5224-34.PMID:9832463DOI:10.1210/endo.139.12.6343.
Idoxifene, a novel selective estrogen receptor modulator, was tested for its effects on bone loss, serum cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat. Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD). In an intervention study, Idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group. Idoxifene reduced total serum cholesterol, which was maximal at 0.5 mg/kg x day. Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of estrogen in intact rats. Histologically, myometrial and endometrial atrophy were observed in both Idoxifene and vehicle-treated Ovx rats. In this report, we also provide molecular-based evidence to support the observations in vivo of a novel selective estrogen receptor modulator (SERM) mechanism of action in bone and endometrial cells. Idoxifene is an agonist through the estrogen response element (ERE) and exhibits similar postreceptor effects to estrogen in bone-forming osteoblasts. Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis. However, Idoxifene differs from estrogen in a tissue-specific manner. In human endometrial cells, where estrogen is a potent agonist through the ERE, Idoxifene has negligible agonist activity. Moreover, Idoxifene was able to block estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study. In the uterus, Idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity. Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that Idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium.
Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer
Ann Oncol 2003 Feb;14(2):233-41.PMID:12562650DOI:10.1093/annonc/mdg097.
Background: More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen. Patients and methods: Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or Idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review. Results: At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for Idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; Idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) >or=6 months] was 34.3% for Idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for Idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms. Conclusions: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.
Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis
Cancer Res 1999 Aug 1;59(15):3646-51.PMID:10446976doi
Idoxifene is a novel selective estrogen (E2) receptor (ER) modulator that is currently in clinical development for the treatment of breast cancer. Compared to tamoxifen, Idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells. Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways. In this study, the abilities of Idoxifene and tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared. The basis for Idoxifene's antitumor activity was examined by comparing the effectiveness of the clinically used transisomer (referred to here as Idoxifene) with its cis-isomer, which has a 50-fold lower relative binding affinity for ER than Idoxifene but similar calmodulin-inhibitory activity. Changes in tumor cell proliferation, apoptosis, and ER-dependent protein expression were studied. Both Idoxifene and tamoxifen significantly inhibited E2-dependent tumor growth, whereas cis-idoxifene had little effect. Withdrawal of E2 support induced significant tumor regression due to impaired cell proliferation (Ki-67 score, 9 versus 51% compared to E2 controls) and induction of apoptosis (3.6 versus 0.9% compared to E2 controls). Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported tumors after 1 week, which was maintained for 3 months with Idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in tumors treated with tamoxifen (0.69%). In contrast, cis-idoxifene had no effect on either cell proliferation or apoptosis. Both tamoxifen and Idoxifene initially induced ER expression, whereas prolonged therapy with tamoxifen significantly reduced progesterone receptor levels. In conclusion, Idoxifene resulted in similar inhibition of E2-dependent MCF-7 xenograft growth compared with tamoxifen, an effect that is mediated via ER rather than through calmodulin. Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of Idoxifene, compared to tamoxifen.
Inhibitory effects of Idoxifene on hepatic fibrosis in rats
Acta Pharmacol Sin 2005 May;26(5):581-6.PMID:15842777DOI:10.1111/j.1745-7254.2005.00082.x.
Aim: To investigate the effects of a tissue-specific selective estrogen receptor modulator, Idoxifene, on hepatic fibrosis in rats. Methods: Hepatic fibrosis was induced by dimethylnitrosamine (DMN) in male rats. The DMN model of hepatic fibrosis and the hepatocytes undergoing oxidative stress were treated with Idoxifene respectively. The effect of Idoxifene on hepatic fibrosis in the DMN model was examined by immunohistochemistry. Effects of Idoxifene on antioxidant enzyme levels of copper, zinc-dependent superoxide dismutase (CuZn-SOD), and cellular glutathione peroxidase (GSHPx) were measured by ELISA. Effects of Idoxifene on activation, proliferation, and apoptosis of culture-activated hepatic stellate cells (HSC) were analysed by immunohistochemistry, bromodeoxyuridine (BrdU) uptake, and flow cytometry, respectively. Results: Idoxifene could markedly suppress DMN-induced hepatic fibrosis in male rats. A treatment of 0.4 mg x kg(-1) x d(-1) of Idoxifene reduced the protein levels of collagen in the DMN model by 41.19% (P<0.05). Protein level of CuZn-SOD and activitiy of GSHPx in liver treated with DMN plus 0.4 mg/kg/d of Idoxifene were 2.65 times (P<0.05) and 2.08 times greater (P<0.05) than that of liver treated with DMN alone respectively. The protein level of CuZn-SOD and activity of GSHPx in cultured rat hepatocytes treated with ferric nitrilotriacetate (FeNTA) plus 1 multiply 10(-7) mol/L of Idoxifene were 3.43 times (P<0.05) and 2.52 times (P<0.05) greater than that treated with FeNTA alone. Idoxifene could inhibit HSC activation. Compared with the control, the uptake of BrdU in HSC cultured with 1 multiply 10(-7) mol/L of Idoxifene was reduced by 51.87 % (P<0.05), and the number of apoptotic HSCs cultured with 1 multiply 10(-7) mol/L of Idoxifene increased by 94.52% (P<0.05). Conclusion: Idoxifene showed inhibitory action on hepatic fibrosis in male rats.
Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes
Dig Dis Sci 2003 Mar;48(3):570-80.PMID:12757172DOI:10.1023/a:1022553119715.
Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and Idoxifene is a tissue-specific selective estrogen-receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in rat models of hepatic fibrosis and that the actions of E2 are mediated through estrogen receptors (ERs). This study reports on the antiapoptotic role of Idoxifene and E2, and the functions of ER subtypes ER-alpha and ER-beta in hepatocytes undergoing oxidative stress. Lipid peroxidation was induced in cultured rat hepatocytes with ferric nitrilotriacetate solution with Idoxifene or E2. Oxidative stress-induced early apoptosis was linked to its ability to inhibit not only the expression of Bcl-2 and Bcl-XL but the production of antioxidant enzymes as well and to stimulate Bad expression. Hepatocytes possessed functional ER-beta, but not ER-alpha, to respond directly to Idoxifene and E2. Idoxifene and E2 suppressed oxidative stress-induced reactive oxygen species generation and lipid peroxidation, and their antiapoptotic effects on the activation of activator protein-1 and nuclear factor-kappaB, the loss of antioxidant enzyme activity, and Bcl-2 family protein expression in early apoptotic hepatocytes were blocked by the pure ER antagonist ICI 182,780. Our results indicate that Idoxifene and E2 could enhance antiapoptotic activity through ER-beta during oxidative damage in hepatocytes.