Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirty years after the introduction of tamoxifen, which was expanded from palliation of metastatic cancer to recent application for chemoprevention, the primacy of this drug as the mainline pharmacological intervention is currently being challenged by the third generation aromatase inhibitors and inactivators. In contrast to the oestrogen receptor blockade provided by tamoxifen, aromatase inhibitors result in deprivation of oestrogens in postmenopausal women both through paracrine/intracrine and endocrine modulation. Experimental evidence has shown a significant (97-99%) reduction of in vivo aromatase activity and an equal or sometimes better antitumour activity compared with megestrol acetate when these drugs are used as second-line treatment for metastatic breast cancer. Recent pivotal studies in first-line settings comparing tamoxifen for metastatic breast cancer and preliminary results from the neoadjuvant trials demonstrate that third generation aromatase inhibitors are superior to tamoxifen. With a better understanding of local tissue production of oestrogen through oestrone sulfatase, which hydrolyses oestrone sulfate to oestrone, and 17-beta-hydroxysteroid dehydrogenase Type 1, which in turn catalyses the reduction of oestrone to oestradiol, more powerful tactics for oestrogen starvation of cancer may be realised in future.
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PMID:Aromatase inhibitors and other novel agents in breast cancer treatment. 1598 53

Steroid sulfatase (STS) is the only well characterized enzyme in human cells that is capable to desulfate estrone 3-sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) as a first step in the conversion of these precursors to active hormones. STS has been found to be highly expressed in estrogen-dependent breast tumors in post-menopausal women and is regarded as a crucial component of the local estrogen production that is required for tumor growth and survival. Inhibitors of STS are expected to block the intra-tumoral estrogen synthesis and, therefore, are considered as potential new therapeutic agents for the treatment of estrogen-dependent cancers of the breast and the endometrium. In this review, we give an overview on the current status in the field of medicinal chemistry of STS inhibitors. Newer developments comprise potent aryl sulfamate-based irreversible inhibitors, and several types of reversible inhibitors. Other directions include compounds with dual mode of action, such as compounds that block both STS and aromatase, or act as STS inhibitors and antiproliferative or antiangiogenic agents at the same time. In particular, these agents featuring an extended mode of action hold promise to be included in the armamentarium to fight endocrine-dependent cancer.
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PMID:Steroid sulfatase inhibitors: their potential in the therapy of breast cancer. 1617 76

It is well known that sex steroids are involved in the growth of breast cancers, and the great majority of breast carcinomas express estrogen (ER), progesterone (PR), and androgen (AR) receptors. In particular, recent studies have demonstrated that estrogens and androgens are locally produced in breast carcinoma tissues, and total blockade of in situ estrogen production potentially leads to an improvement in prognosis of breast cancer patients. Therefore, it is important to obtain a better understanding of sex steroid-producing enzymes in breast carcinoma tissues. In this review, we summarize recent studies on the expression and regulation of enzymes related to intratumoral production of estrogens (aromatase, 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1), and steroid sulfatase (STS) etc) and androgens (17betaHSD5 and 5alpha-reductase) in human breast carcinoma tissues, and discuss the biological and/or clinical significance of these enzymes. The cellular localization of aromatase in breast carcinoma tissues still remains controversial. Therefore, we examined localization of aromatase mRNA in breast carcinoma tissues by laser capture microdissection/real time-polymerase chain reaction. Aromatase mRNA expression was detected in both carcinoma and intratumoral stromal cells, and the expression level of aromatase mRNA was higher in intratumoral stromal cells than in carcinoma cells in the cases examined. We also examined an association among the immunoreactivity of enzymes related to intratumoral estrogen production and ERs in breast carcinoma tissues, but no significant association was detected. Therefore, the enzymes responsible for the intratumoral production of estrogen may not always be the same among breast cancer patients, and not only aromatase but also other enzymes such as STS and 17betaHSD1 may have important therapeutic potential as targets for endocrine therapy in breast cancer patients.
Endocr Relat Cancer 2005 Dec
PMID:Sex steroid-producing enzymes in human breast cancer. 1632 18

Estrogen sulfatase is a microsomal enzyme and is ubiquitously distributed in several mammalian tissues, among which the liver, placenta, and endocrine tissues exhibit relatively high activity. Because the major circulating precursors of estrogen are estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, estrogen sulfatase plays an important role not only in their incorporation and metabolism, but also in the controls of estrogen activity by regulating the binding potential of estrogen as to its receptor through sulfoconjugation and desulfation reactions. Accordingly, an increase in sulfoconjugation through transfection of the sulfotransferase gene or inhibition of estrogen sulfatase by specific inhibitors has been successfully applied to abolish the estrogen activity in estrogen-dependent breast cancer- and uterine endometrial adenocarcinoma-derived cells. Inhibitors of estrogen sulfatase are expected to be developed as new drugs for estrogen-dependent cancer therapy, particularly in postmenopausal women.
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PMID:Estrogen sulfatase. 1639 56

3,3'-Diindolylmethane (DIM) is a major in vivo product of the cancer preventative agent indole-3-carbinol that is found in vegetables of the genus Brassica. Here, we report on the metabolic fate of radiolabeled DIM in MCF-7 cells. DIM was slowly metabolized to several sulfate conjugates of oxidized DIM products that were primarily detected in the medium. The radioactivity detected in cells was predominantly unmodified DIM (81-93%) at all time intervals up to 72 h treatment. Co-treatment of MCF-7 cells with quercetin slowed the rate that oxidized DIM products accumulated in the medium, while indole[3,2-b]carbazole (ICZ) co-treatment accelerated their production. ICZ is an inducer of P450 1A2, while quercetin is a specific inhibitor of this isoform, suggesting that P450 1A2 is primarily responsible for the oxidation of DIM, probably through 2,3-epoxidation similar to 3-methylindole. Sulfate conjugates of oxidized DIM metabolites were cleaved by sulfatase digestion and identified by LC/MS as 3-(1H-indole-3-ylmethyl)-2-oxindole (2-ox-DIM), bis(1H-indol-3-yl)methanol (3-methylenehydroxy-DIM), 3-[hydroxy-(1H-indol-3-yl)-methyl]-1,3-dihydro-2-oxindole (3-methylenehydroxy-2-ox-DIM), and 3-hydroxy-3-(1H-indole-3-ylmethyl)-2-oxindole (3-hydroxy-2-ox-DIM). Derivatives of 2-ox-DIM represented greater than 30% of the radioactivity in the sulfatase-digested medium. Although oxindole formation was the primary metabolic pathway in MCF-7 cells, synthetic 2-ox-DIM was inactive in a 4-ERE-luciferase reporter assay and, therefore, probably not responsible for the estrogenic activity previously observed for DIM. Unmodified DIM rapidly accumulated in the nuclear membranes representing approximately 35-40% of the radioactivity after 0.5-2 h treatment. Uptake of radiolabeled DIM appeared to be a passive partitioning into the nuclear membranes and was not dependent upon the cell cytosol. The nuclear uptake of DIM was not saturable and could not be blocked by pretreatment with unlabeled DIM (100 microM). Further, treatments in serum-free medium increased the uptake of radiolabeled DIM by the MCF-7 cells. These findings show that the uptake of DIM by membranes significantly increases its localized concentration, which may contribute to its biological activities.
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PMID:Fate of 3,3'-diindolylmethane in cultured MCF-7 human breast cancer cells. 1654 49

Expression of the estrogen-synthesizing genes aromatase, steroid sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type1 (17beta-HSD(1)) has been shown to be up-regulated in primary breast cancer tissue but their expression status in metastatic tumor tissue has yet to be determined. The mRNA expression levels of the three estrogen-synthesizing genes as well as of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and cyclooxygenase (COX)-2, all of which have been reported to up-regulate the estrogen-synthesizing genes, were determined by means of a real-time PCR assay in 100 primary breast cancer tissues and 15 soft tissue metastases. In addition, PCR-gel electrophoresis was used to determine the proportion (%) of promoter (l.4, l.3, Pll and l.7) usage of aromatase. Aromatase and STS mRNA levels were significantly (P=0.04 and P=0.03, respectively) higher in soft tissue metastases than in primary tumors, while 17beta-HSD(1) mRNA levels tended (P=0.09) to be higher. The proportions of the promoter usages were very similar for primary tumors and soft tissue metastases, and the mRNA levels of TNF-alpha, IL-6 and COX-2 were not significantly different. Levels of aromatase, STS and 17beta-HSD(1) mRNA are up-regulated in soft tissue metastases compared to those in primary tumors, suggesting that intra-tumoral estrogen synthesis may play a significant role in the growth stimulation of tumor cells in soft tissue metastases as in primary tumors. TNF-alpha, IL-6 and COX-2, on the other hand, are unlikely to be implicated in this up-regulation.
Cancer Lett 2006 Nov 08
PMID:Quantitative analysis of aromatase, sulfatase and 17beta-HSD(1) mRNA expression in soft tissue metastases of breast cancer. 1655 83

Macroautophagy (hereafter referred to as autophagy) has emerged as a key tumor suppressor pathway. During this process, the cytosolic constituents are sequestered into autophagosomes, which subsequently fuse with lysosomes to become autolysosomes where their contents are finally degraded. Although a reduced autophagy has been shown in human tumors or in response to oncogenes and carcinogens, the underlying mechanism(s) remain(s) unknown. Here, we show that widely used carcinogen Lindane promotes vacuolation of Sertoli cells. By electron and immunofluorescent microscopy analyses, we showed that these structures are acid autolysosomes, containing cellular debris, and labeled by LC3, Rab7, and LAMP1, markers of autophagosomes, late endosomes, and lysosomes, respectively. Such Lindane-induced vacuolation results from significant delay in autophagy degradation, in relation with a decline of the lysosomal activity of aryl sulfatase A. At molecular level, we show that this defect in autolysosomal maturation is independent of mammalian target of rapamycin and p38 inhibitions. Rather, the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is required for Lindane to disrupt the autophagic pathway. Most importantly, we provide the first evidence that sustained activation of ERK pathway is sufficient to commit cell to autophagic vacuolation. Taken together, these findings strongly support that the aberrant sustained activation of ERK by the carcinogen Lindane disrupts the maturation of autophagosomes into functional autolysosomes. Our findings therefore suggest the possibility that high constitutive ERK activity found in all cancers may provide a malignant advantage by impeding the tumor suppressive function of autophagy.
Cancer Res 2006 Jul 01
PMID:Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. 1710 81

Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38 microM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 microM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 microM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.
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PMID:3,17-disubstituted 2-alkylestra-1,3,5(10)-trien-3-ol derivatives: synthesis, in vitro and in vivo anticancer activity. 1769 19

Progestins exert their progestational activity by binding to the progesterone receptor (form A, the most active and form B, the less active) and may also interact with other steroid receptors (androgen, glucocorticoid, mineralocorticoid, estrogen). They can have important effects in other tissues besides the endometrium, including the breast, liver, bone and brain. The biological responses of progestins cover a very large domain: lipids, carbohydrates, proteins, water and electrolyte regulation, hemostasis, fibrinolysis, and cardiovascular and immunological systems. At present, more than 200 progestin compounds have been synthesized, but the biological response could be different from one to another depending on their structure, metabolism, receptor affinity, experimental conditions, target tissue or cell line, as well as the biological response considered. There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E(2)) from circulating precursors. Two principal pathways are implicated in the final steps of E(2) formation in breast cancer tissue: the 'aromatase pathway', which transforms androgens into estrogens, and the 'sulfatase pathway', which converts estrone sulfate (E(1)S) into estrone (E(1)) via estrone sulfatase. The final step is the conversion of weak E(1) to the potent biologically active E(2) via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. It has been demonstrated that various progestins (e.g. nomegestrol acetate, medrogestone, promegestone) as well as tibolone and their metabolites can block the enzymes involved in E(2) bioformation (sulfatase, 17beta-hydroxysteroid dehydrogenase) in breast cancer cells. These substances can also stimulate the sulfotransferase activity which converts estrogens into the biologically inactive sulfates. The action of progestins in breast cancer is very controversial; some studies indicate an increase in breast cancer incidence, others show no difference and still others a significant decrease. Progestin action can also be a function of combination with other molecules (e.g. estrogens). In order to clarify and better understand the response of progestins in breast cancer (incidence, mortality), as well as in hormone replacement therapy or endocrine dysfunction, new clinical trials are needed studying other progestins as a function of the dose and period of treatment.
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PMID:Progestins and breast cancer. 1794 37

The endocrine system and its steroids have long been thought to be instrumental in the etiology of breast cancer. A large proportion of cancerous breast tissues have been shown to express estrogen (ER), androgen (AR) and progesterone (PR) receptors. It is through these receptors that steroid hormones can exert their mitogenic effects. The local biosynthesis of estrogens is believed to play an integral part in the development of hormone-dependent breast cancer and recent studies on the use of inhibitors to block this steroid production has yielded an improvement of prognosis in breast cancer patients. Consequently, the understanding of the enzymes involved in the synthesis and metabolism of estrogens in breast cancer is paramount to treating this malignancy. This review examines the biological and clinical relevance of three key endocrine enzymes: steroid sulfatase (STS), aromatase (Arom), and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type-1. The importance of the over expression and increased activity of these enzymes in breast tissue and on breast cancer is discussed. Importantly, the intratumoral biosynthesis of estrogens is examined in detail. The effects of new inhibitors of these enzymes on the growth of hormone-dependent breast cancer will also be investigated. First and second generation STS inhibitors and third generation aromatase inhibitors are showing significant promise, whereas inhibitors for 17beta-HSD type-1 are still at an early stage. However, such endocrine therapy that is currently being explored has shown promising results for patients with hormone-dependent breast cancer.
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PMID:Steroid metabolism in breast cancer. 1827 77


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