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Results for “Selective Estrogen Receptor Modulators”

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PubMed2003

Differential effects of raloxifene, tamoxifen and fulvestrant on a murine mammary carcinoma.

The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer. The effects of these compounds on cell proliferation were studied in primary cultures of a progestin-dependent mammary carcinoma tumor line, in the presence of medroxyprogesterone acetate (MPA) or 17-beta-estradiol (E2). In in vivo studies the tumor was inoculated subcutaneously in BALB/c female mice treated with 20 mg MPA depot. Raloxifene (12.5 mg/kg) or tamoxifen (5 mg/kg) were administered in daily doses or E2 silastic pellets (5 mg) were implanted. When the tumors reached about 25-50 mm2 MPA was removed in half of the animals. E2 induced complete tumor regressions, tamoxifen inhibited tumor growth in vivo while raloxifene disclosed proliferative effects in animals in which MPA had been removed. In vitro, E2 inhibited cell proliferation at concentrations higher than 10(-14)M. Raloxifene and fulvestrant, but not tamoxifen, partially reverted E2-induced inhibition. Fulvestrant and tamoxifen inhibited MPA-induced cell proliferation while raloxifene had a stimulatory effect. Tamoxifen and E2 increased, raloxifene induced no effect, and fulvestrant significantly decreased PR expression. In this study we provide evidence for differential effects of tamoxifen and raloxifene on experimental mammary tumors. Since raloxifene is under evaluation for use in breast cancer prevention, these results may have important clinical implications.

Animals↗

PubMed2003

Dopamine resistance of prolactinomas.

Resistance to dopamine agonists can be defined with respect to failure to normalize PRL levels and failure to decrease tumor size by > or = 50%. Using these definitions, failure to normalize PRL levels is seen in 24% of those treated with bromocriptine, 13% of those treated with pergolide and 11% of those treated with cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. Studies of in vitro cell preparations show that the D2 receptors of resistant tumors are decreased in number but have normal affinity. Treatment approaches for resistant patients include switching to another dopamine agonist and raising the dose of the drug as long as there is continued response to the dose increases and no adverse effects. Transsphenoidal surgery can also be done. If fertility is desired, clomiphene, gonadotropins, and GnRH are also options. If fertility is not desired, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. However, in many cases modest or even no reduction may be acceptable long-term as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.

Bromocriptine↗

PubMed2003

Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients.

Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus-pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus-pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.

Aged↗

PubMed2004

[Aromatase inhibitors in the adjuvant therapy of breast carcinomas].

Hormonal therapies have been used in the adjuvant therapy of breast cancer for decades. Tamoxifen, a selective estrogen receptor modulator, is the current standard therapy. It reduces the risk of recurrence by about one half Only recently, new aromatase inhibitors (anastrozole, letrozole, exemestane) have been competing with tamoxifen; these drugs are superior to tamoxifen in advanced breast cancer. Two recent trials are discussed: Anastrozole reduced the short-term risk of recurrent disease more efficiently than tamoxifen. The use of letrozole after five years of adjuvant tamoxifen treatment further reduced the risk of recurrence. Numerous side-effects, notably endometrial cancer and thromboembolic disease, were less frequent with aromatase inhibitors whereas the risk of osteoporotic fractures increased substantially. The positive preliminary results of these and other trials are discussed: At present, the use of aromatase inhibitors is not yet recommended on a routine basis. Future trial results will allow a more complete assessment of the efficacy and toxicity of aromatase inhibitors.

Anastrozole↗

PubMed2001

Effects of idoxifene and estradiol on NF-kappaB activation in cultured rat hepatocytes undergoing oxidative stress.

BACKGROUND/AIMS: Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor kappaB (NF-kappaB) is a key transcription factor that induces multiple genes in response to inflammation or oxidative stress. The aim of this study was to explore the inhibitory effects of idoxifene and estradiol on NF-kappaB activation in hepatocytes in a state of oxidative stress. METHODS: Lipid peroxidation was induced in cultured rat hepatocytes by incubation with ferric nitrilotriacetate solution. NF-kappaB activity was evaluated by electrophoretic mobility shift assay. RESULTS: The oxidative stress-induced activation of NF-kappaB and degradation of IkappaB-alpha were maximal at 3-5 h, with an increase in lactate dehydrogenase (LDH) and malondialdehyde (MDA) secretion into the culture medium. Treatment with idoxifene and estradiol inhibited IkappaB-alpha degradation and NF-kappaB activation through the attenuation of hepatocyte oxidative bursts and decreased extracellular levels of LDH and MDA. In addition, idoxifene and estradiol inhibited lipid peroxidation in rat liver mitochondria. A potent NF-kappaB inhibitor, pyrrolidine dithiocarbamate, prevented NF-kappaB activation by inhibition of IkappaB-alpha degradation and decreased LDH and MDA levels, suggesting that NF-kappaB might be a regulator in a genetic response to increase oxidative stress-induced hepatic injury. CONCLUSIONS: These findings suggest that idoxifene and estradiol function as antioxidants and protect hepatocytes from inflammatory cell injury.

Animals↗

PubMed2004

Effect of red clover-derived isoflavone supplementation on insulin-like growth factor, lipid and antioxidant status in healthy female volunteers: a pilot study.

BACKGROUND: Isoflavones are estrogen-like plant compounds that may protect against cardiovascular disease and endocrine-responsive cancer. Isoflavones may, because of their ability to act as selective estrogen receptor modulators, alter insulin-like growth factor (IGF) status. OBJECTIVE: The aim of this study was to assess the effect of 1-month isoflavone supplementation (86 mg/day red clover-derived isoflavones) on IGF status. DESIGN AND SUBJECTS: Healthy pre- (n=16) and postmenopausal (n=7) women were invited to take part in a randomised, placebo-controlled crossover study with a minimum 2-month washout period. RESULTS: : For premenopausal subjects, the change in IGF-1, IGF-BP1 and IGF-BP3 assessed at different points of the menstrual cycle did not differ between isoflavone and placebo phase. However, the change in IGF-1, when examined pre- and post-supplementation, was nonsignificantly reduced (P=0.06) on the isoflavone supplement compared to placebo. For postmenopausal subjects, the change in IGF-1, IGF-BP1 and IGFBP-3 concentrations over the supplementation period did not differ between isoflavone or placebo phase. Isoflavones increased HDL in postmenopausal women compared to placebo (P=0.02) but did not alter either cholesterol or triacylglycerol concentrations, and had no effect on antioxidant status. CONCLUSIONS: This study shows that 1-month supplementation with red clover isoflavones has a positive effect on HDL cholesterol, but at most a small effect on IGF status in premenopausal and no effect in postmenopausal subjects. Further studies are required to ascertain the role these dietary compounds may have to play in breast cancer prevention.

Adult↗

PubMed2004

Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques.

In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

Animals↗

PubMed2005

Raloxifene treatment enhances brain activation during recognition of familiar items: a pharmacological fMRI study in healthy elderly males.

Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n=28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n=14) or placebo (n=14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z=3.9) and right inferior prefrontal cortex (Z=3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p=0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of context-dependency. The validity of these predictions can be tested in large-scale clinical trials.

Aged↗

PubMed2000

Hormonal Therapy and Chemoprevention.

Hormone replacement therapy (HRT) can increase the quality as well as the length of life, but a prolonged use can also increase the risk of breast cancer. The combination of HRT and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. A post hoc analysis of the Italian Tamoxifen Prevention Study showed a borderline significant reduction of breast cancer among women who were on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Recent studies suggest that the standard dose of tamoxifen may be reduced to one-quarter (i.e., 10 mg every other day) without loss of its beneficial biological effects. Since the endometrial effect of tamoxifen seems to be both dose and time dependent, a dose reduction could substantially reduce the risk of endometrial cancer while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could also minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and urogenital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. Notably, in the National Surgical Adjuvant Breast Project (NSABP) P-1 trial, women ages 50 or younger had no increased incidence of adverse events, including endometrial cancer and venous thromboembolic events. One possible explanation for the lack of toxicity in premenopause is the presence of adequate circulating estrogen levels which prevent tamoxifen to act as an estrogen agonist at these target tissues. Moreover, data from the current Italian tamoxifen prevention trial indicate that the compliance was substantially higher for de novo and current HRT users as compared to women who never received HRT during the study. The combination of HRT and tamoxifen at low doses could thus reduce the risks and side effects while retaining the benefits of either agent.

Journal Article↗

PubMedDate not supplied

Tamoxifen in the management of pseudoangiomatous stromal hyperplasia.

Pseudoangiomatous stromal hyperplasia (PASH) is a relatively uncommon histologic finding in breast specimens. The clinicopathologic spectrum of this disease entity can range from a focal nonsignificant microscopic finding to a dominant palpable breast mass. To confirm the diagnosis, a biopsy is required primarily to distinguish PASH from a low-grade angiosarcoma. The mammographic description of PASH is a round or ovoid, circumscribed or partially circumscribed mass. The sonographic feature is a hypoechoic mass. PASH is similar to a fibroadenoma in clinical and imaging features. Progressive breast enlargement associated with engorgement, cyclical breast pain, and burning sensation is of significant concern for some women. The management of the palpable mass and associated symptoms has included excisional biopsy, often leading to recurrent excisions and even mastectomy. This report documents an impressive response to tamoxifen in a patient with PASH presenting with breast enlargement, pain, and breast masses. To our knowledge, there are no reports on the use of tamoxifen or other selective estrogen receptor modulators in the management of this benign breast condition.

Adult↗

PubMed2002

[Guidelines for drug therapy of postmenopausal osteoporosis].

Osteoporosis is known as a condition characterized by low bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and a consequent susceptibility to fracture. Osteoporosis has its highest rate of occurrence in postmenopausal women, and in Western countries it has been estimated that for white women aged fifty, the life-time risk of developing an osteoporotic fracture is nearly 40%. Given the consequences of osteoporosis, the most important goal of therapy is to prevent fractures. In Austria, several pharmacologic options for treatment of osteoporosis are available, including bisphosphonates (alendronate, etidronate, risedronate), selective estrogen receptor modulators (raloxifene), calcitonins (salm-calcitonin, elcatonin), fluorides (sodium-fluoride, monofluorophosphate), anabolic steroids (nandrolone-decanoate), steroid derivates (tibolone), estrogen and hormone replacement therapy. An evidence-based evaluation of these treatment options clearly indicates that alendronate, risedronate and raloxifene sufficiently reduce the risk of vertebral fractures. There is less evidence for reduction of vertebral fracture risk for etidronate, calcitonin, estrogen replacement therapy or hormone replacement therapy. Only alendronate and risedronate have been shown to reduce the risk of hip fractures. Calcium and vitamin D are useful adjuncts to any specific treatment for osteoporosis, particularly when Calcium and vitamin D deficiencies have been diagnosed. Also, there is good evidence that in women with Calcium and vitamin D deficiency, a combination of Calcium and vitamin D may reduce the risk of non-vertebral fractures. There is no evidence so far that a combination therapy of antiresorptive drugs would result in reduced fracture risk.

Adult↗

PubMed2003

Phytoestrogens: recent developments.

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Based on their chemical structure, phytoestrogens can be classified into four main groups, i. e., isoflavonoids, flavonoids, stilbenes, and lignans. For each group, the chemistry, dietary sources and biotransformation of the most interesting compounds will be discussed. Since phytoestrogens are structurally very similar to the estrogen 17beta-estradiol, they may exhibit selective estrogen receptor modulating activities. Therefore, special attention will be given to the hormonal effects of various isoflavonoids, including genistein, daidzein, coumestrol and equol, several prenylated flavonoids, especially 8-prenylnaringenin, and the stilbene resveratrol. Furthermore, their non-hormonal effects will be discussed briefly. Finally, the latest developments on the potential protective properties of phytoestrogens and phytoestrogen-containing foods against hormone-dependent breast and prostate cancers and cardiovascular diseases, and as estrogen replacement therapy for postmenopausal women will be discussed.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Uterine effects of the phytoestrogen 6-(1,1-dimethylallyl)naringenin in rats.

Phytoestrogens are discussed as candidate substances to treat symptoms related to estrogen deficiency. In in vitro experiments, the naturally occurring flavonoid 6-(1,1-dimethylallyl)naringenin (6-DMAN) emerged as one of the most potent phytoestrogenic substances. 6-DMAN is not as well characterized as other flavonoids (8-prenylnaringenin) or isoflavones (genistein). We tested 6-DMAN for the first time in vivo, in a dose-dependent three-day uterotropic assay in ovariectomized Wistar rats, using 6-DMAN at three different concentrations (1.5 mg/kg; 7.5 mg/kg and 15 mg/kg BW/d). Estradiol (E2; 10 microg/kg BW/d) and the carrier castor oil were used as positive and negative controls. 6-DMAN did not have any effect on uterine wet weight, while the positive control E2 did. In contrast, 6-DMAN stimulated uterine mRNA expression of estrogen responsive genes in ovariectomized rats. Estrogen receptor alpha and beta mRNA were expressed in the uterus. They mediate the expression of genes with an estrogen responsive element in the promoter, e. g., complement C3 and the progesterone receptor. Therefore, we analyzed the expression of the above-mentioned genes in three different concentrations. 6-DMAN up-regulated progesterone receptor and particularly complement C3 mRNA expression however, less pronounced than E2. In conclusion, we demonstrated for the first time estrogenic activities of 6-DMAN in vivo. Surprisingly, although 6-DMAN regulated estrogen responsive gene expression, there was no uterine wet weight gain. These findings make 6-DMAN a very interesting candidate substance for further characterization, as it potentially represents a naturally occurring selective estrogen receptor modulator.

Animals↗

PubMed2005

Female sexual dysfunction and use of hormone therapy in postmenopausal women.

Sexual dysfunction is a common problem for women of all ages and remains an important aspect of women's health following menopause. For postmenopausal women, the evaluation and management of sexual dysfunction differs from that of younger women because the etiology is often linked to the diminished levels of sex hormones. Female sexual function is highly complex and deeply influenced by nonhormonal factors such as emotional intimacy and culture. Our understanding of this important area of women's health remains inadequate, and much more research needs to be performed before definitive conclusions can be made. Existing data allow for some preliminary observations. It appears that lack of estrogen may lead to sexual dysfunction primarily by causing vaginal atrophy and dyspareunia. These symptoms may be treated by systemic or local estrogen therapy. Conversely, androgen deficiency appears to be most strongly linked to diminished sexual desire. Growing evidence indicates that administration of androgens may be beneficial in such situations. Other agents that use sex hormone receptors, such as selective estrogen receptor modulators and tibolone, also may affect sexual function.

Androgens↗

PubMed2000

Tamoxifen prevents bone loss in castrated male mice.

The selective estrogen receptor modulator tamoxifen was administered to intact and castrated male mice, and its effects on tibial bones and circulatory calcium, phosphate and testosterone were compared with controls and castrated animals. Tamoxifen in a dose used in humans for treatment of breast cancer decreased the weight of seminal vesicles, an organ which is highly sensitive to the androgenic effect, decreased the concentration of testosterone, but did not have any negative effect on bone density or mineral content in intact mice. When castrated mice with extraordinarily low concentrations of testosterone and weights of seminal vesicles were treated with tamoxifen, the changes in bone density and bone mineral resulting from castration were not only entirely prevented, but increased above the values of intact mice. At the same time, cortical bone was lost in orchidectomized mice, and this decrease in cortical thickness of femur was completely prevented by tamoxifen treatment. Pharmacological therapy with estrogen agonist on bone, tamoxifen in androgen deficient adult male mice prevents bone loss.

Animals↗

PubMed1999

Thrombophilic state in breast cancer.

Tumor cell metastasis and thrombosis are the major causes of death in cancer patients. Thrombosis in cancer patients may occur when physiologic antithrombotic systems are defective or when prothrombotic activities defeat normal physiologic antithrombotic mechanisms. Malignancies by themselves may already predispose to a hypercoagulable state in cancer patients. Tumor cells can either directly activate the blood clotting system or indirectly stimulate mononuclear cells to synthesize and express various procoagulants, subsequently leading to prothrombin activation, fibrin formation, and generation of a thrombus. In addition, other comorbid predisposing factors effecting thrombosis in cancer patients have to be considered, including surgery, bed rest, infection, long-term indwelling central venous catheters, anticoagulation, and chemotoxic or steroidal anticancer drugs used in adjuvant or palliative cancer treatment. Reliable information on the incidence of thromboembolism in cancer patients is available for breast cancer; less data have been reported for other malignancies. Chemo- and/or hormone therapy in patients with primary or metastatic breast cancer is associated with an increased thromboembolic risk, although the benefits of treatment far outweigh the risks. The current literature discussing the effect of chemo/hormone therapy on blood clotting factors and the associated risk of thrombosis is reviewed, with emphasis on new developments in the area of tissue-specific SERMs (selective estrogen receptor modulators). SERMs are employed as adjuvant therapy in primary breast cancer and in the palliation of advanced breast cancer and may be clinically useful as potential substitutes for long-term hormone replacement therapy, in the treatment of osteoporosis, and for cancer prevention therapy.

Antineoplastic Agents↗

PubMed2001

Induction of endothelial nitric-oxide synthase phosphorylation by the raloxifene analog LY117018 is differentially mediated by Akt and extracellular signal-regulated protein kinase in vascular endothelial cells.

Raloxifene is a tissue-selective estrogen receptor modulator. The effect of estrogen on cardiovascular disease is mainly dependent on direct actions on the vascular wall involving activation of endothelial nitric oxide synthase (eNOS) via Akt and extracellular signal-regulated protein kinase (ERK) cascades. Although raloxifene is also known to activate eNOS in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells and simian virus 40-transformed rat lung vascular endothelial cells (TRLECs), the raloxifene analog LY117018 caused acute phosphorylation of eNOS that was unaffected by actinomycin D and was blocked by the pure estrogen receptor antagonist ICI182,780. Activation of Akt by raloxifene reached a plateau at 15-30 min and declined thereafter, a similar time frame to that of Akt activation by 17beta-estradiol. On the other hand, both activation and phosphorylation of ERK by raloxifene showed a biphasic pattern (peaks at 5 min and 1 h), whereas ERK activation and phosphorylation by 17beta-estradiol reached a plateau at 5 min and declined thereafter. A MEK inhibitor, PD98059, had no effect on the raloxifene-induced Akt activity, suggesting an absence of cross-talk between the ERK and Akt cascades. Either exogenous expression of a dominant-negative Akt or pretreatment of TRLECs with PD98059 decreased the raloxifene-induced eNOS phosphorylation. Moreover, raloxifene stimulated the activation of Akt, ERK, and eNOS in Chinese hamster ovary cells expressing estrogen receptor alpha but not Chinese hamster ovary cells expressing estrogen receptor beta. Our findings suggest that raloxifene-induced eNOS phosphorylation is mediated by estrogen receptor alpha via a nongenomic mechanism and is differentially mediated by Akt- and ERK-dependent cascades.

Animals↗

PubMed2002

Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells.

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.

Amino Acid Chloromethyl Ketones↗