Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential

Thomas, Mark; Potter, Barry V. L.

doi:10.1016/j.jsbmb.2015.03.012

Cited by 38 publications

(41 citation statements)

References 88 publications

(84 reference statements)

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“…Thus, the pharmacological inhibition of certain enzymes which catalyze the formation of key molecules of cell proliferation results in beneficial therapeutic effects during the treatment of hormone-dependent carcinomas. One of these enzymes is steroid sulfatase (STS) which plays an important role not only in the formation of estrone from estrone sulphate, but also in the production of dehydroepiandrosterone (DHEA) and androstenediol from dehydroepiandrosterone sulphate (DHEAS) [70]. These androgens may contribute to excessive cell proliferation in hormone-dependent breast cancers, especially in menopausal women.…”

Section: Steroid Sulfatase Inhibitorsmentioning

confidence: 99%

“…This dual mechanism of action is thought to be beneficial in therapy. Usually, these molecules are 2-substituted derivatives of EMATE or E2MATE, occasionally accompanied by modification(s) in the D-ring of the steroidal skeleton [70]. From another point of view, some of them can be regarded as sulfamoylated derivatives of 2-ME2 and its analogues, blurring the frontier between these pharmacological groups [6].…”

Section: Steroid Sulfatase Inhibitorsmentioning

confidence: 99%

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Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Minorics

Zupkó

2018

ACAMC

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Research of steroidal compounds as anticancer agents started almost 50 years ago. During the past decades, several innovative new steroids, like cyproterone, finasteride, estramustin, exemestane and fulvestrant have successfully become a part of routine clinical practice. Meanwhile, a vast amount of new information have accumulated about the functions of the endogenous steroid system (including the characterization of enzymes, receptors, transcription pathways, etc.) and about the role of steroids in carcinogenesis. Therefore, it is regularly required to review the latest published results, focusing on a well-defined part within this research field that has definitely developed into a highly diversified speciality by now. Herein, we make an attempt to summarize the most recent results reported about anticancer agents of estrane backbone, focusing on their mechanisms of action and their structure-activity relationships. Due to the vast number and various accessibilities of scientific publications, neither other reviews nor this one can be considered as absolutely exhaustive. In spite of these restrictive factors, the current review makes a good opportunity to define the recent scientific trends in the field of estradiol-related anticancer agents.

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Section: Steroid Sulfatase Inhibitorsmentioning

confidence: 99%

Section: Steroid Sulfatase Inhibitorsmentioning

confidence: 99%

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Minorics

Zupkó

2018

ACAMC

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“…Indeed, STS inhibitors have been successfully tested in preclinical and animal models of hormone-dependent cancers (for an extensive review on E1 sulfatase inhibitors and their efficacy in animal and human tumor models, see Thomas and Potter, 2015; Rižner, 2016). Irosustat (STX64) is a potent tricylic coumarin-based sulfamate that irreversibly blocks STS activity, and it has been examined in phase II clinical trials for the treatment of patients with advanced hormone-dependent breast and endometrial cancers (Stanway et al, 2007).…”

Section: Pharmacological Interventions That Target Intracrine Actionsmentioning

confidence: 99%

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

2017

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Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.Keywords: sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase, transporters, OATP, ABC-transporter HORMONE-DEPENDENT CANCERSSteroid hormones have important roles in human physiology, and the disruption of androgen, estrogen, and progesterone actions are implicated in the development of hormone-dependent cancers and benign hormone-dependent diseases. Hormone-dependent cancers include prostate, breast, endometrial, and ovarian cancers, which comprise more than 20% of all cancers in humans, and more than 35% of cancers in women (Ferlay et al., 2013). Indeed, in women, breast cancer is the most frequent cancer in the developed world. In 2012, 1,671,149 new cases of breast cancer were estimated worldwide, with 521,907 associated deaths. In the developed world, endometrial cancer is the most common among gynecological cancers. Worldwide, there were 319,605 new cases and 76,160 deaths from endometrial cancer in 2012 alone (Ferlay et al., 2013). The most deadly of the hormone-dependent cancers is ovarian cancer. Worldwide, there were 238,719 new cases and 151,905 deaths from ovarian cancer in 2012 (Ferlay et al., 2013).

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“…The development of STS inhibitors started in the 1990s, and to date, this has led to two compounds that have entered clinical trials (Poirier, 2015 ). STS inhibitors have been developed by several research groups and several pharmaceutical companies, and the current status of this field has been a topic of several educative reviews in the last few years (Mostafa and Taylor, 2013 ; Sadozai, 2013 ; Thomas and Potter, 2013 , 2015 ; Williams, 2013 ; Poirier, 2015 ). In general, the large number of STS inhibitors known to date can be divided into steroidal and nonsteroidal compounds, and further into sulfomoylated and nonsulfomoylated compounds (Maltais and Poirier, 2011 ).…”

Section: Sulfatase Inhibitors and Clinical Trialsmentioning

confidence: 99%

“…Among the steroidal compounds, estrogen O-sulfamates have been the most intensively studied in in-vitro and in-vivo models. These have included E1-3-O-sulfamate (EMATE) and E2-3-O-sulfamate (E2MATE), where EMATE was identified as the first irreversible STS inhibitor, although it was originally developed as a prodrug for estrogen replacement therapy (Sadozai, 2013 ; Thomas and Potter, 2015 ).…”

Section: Sulfatase Inhibitors and Clinical Trialsmentioning

confidence: 99%

The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

Rižner

2016

Front. Pharmacol.

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Gynecological diseases such as endometriosis, adenomyosis and uterine fibroids, and gynecological cancers including endometrial cancer and ovarian cancer, affect a large proportion of women. These diseases are estrogen dependent, and their progression often depends on local estrogen formation. In peripheral tissues, estrogens can be formed from the inactive precursors dehydroepiandrosterone sulfate and estrone sulfate. Sulfatase and sulfotransferases have pivotal roles in these processes, where sulfatase hydrolyzes estrone sulfate to estrone, and dehydroepiandrosterone sulfate to dehydroepiandrosterone, and sulfotransferases catalyze the reverse reactions. Further activation of estrone to the most potent estrogen, estradiol, is catalyzed by 17-ketosteroid reductases, while estradiol can also be formed from dehydroepiandrosterone by the sequential actions of 3β-hydroxysteroid dehydrogenase-Δ4-isomerase, aromatase, and 17-ketosteroid reductase. This review introduces the sulfatase and sulfotransferase enzymes, in terms of their structures and reaction mechanisms, and the regulation and different transcripts of their genes, together with the importance of their currently known single nucleotide polymorphisms. Data on expression of sulfatase and sulfotransferases in gynecological diseases are also reviewed. There are often unchanged mRNA and protein levels in diseased tissue, with higher sulfatase activities in cancerous endometrium, ovarian cancer cell lines, and adenomyosis. This can be indicative of a disturbed balance between the sulfatase and sulfotransferases enzymes, defining the potential for sulfatase as a drug target for treatment of gynecological diseases. Finally, clinical trials with sulfatase inhibitors are discussed, where two inhibitors have already concluded phase II trials, although so far with no convincing clinical outcomes for patients with endometrial cancer and endometriosis.

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Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential

Cited by 38 publications

References 88 publications

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

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