Article

Estrone sulfatase and its inhibitors.

Department of Pharmacy, School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT12EE, UK.
Anti-cancer agents in medicinal chemistry 08/2009; 9(6):599-612.
Source: PubMed

ABSTRACT A high proportion (approximately 40%) of breast cancers are hormone-dependent and it is the female hormone estradiol (E2) that is believed to play a key role in the initiation, promotion and progression of this disease. In the fight against this disease, compounds which are potent inhibitors of the cytochrome P-450 enzyme aromatase (AR) (which catalyses the conversion of the C19 androgens to the C18 estrogens) have been the major target. However, the administration of AR inhibitors alone does not prevent the localised biosynthesis of estrone (E1) (and therefore the subsequent synthesis of E2) within breast tumour cells via alternative non-AR routes. This has therefore been the major impetus for the development of steroid sulfatase (E1STS) inhibitors. The E1STS enzyme regulates the formation of E1 from estrone sulfate (E1S), a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The STS enzyme has also been shown to catalyse the formation of dehydroepiandrosterone (DHEA) from DHEA-sulfate (DHEAS). This is important since DHEA can be converted to 5-androstene-3beta,17beta-diol, which has been shown to possess weak estrogenic properties, however, due to the high concentration of this steroid, it is able to stimulate the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent E1STS inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone-dependent breast cancer. The review therefore summarises the work that has been undertaken todate.

1 Bookmark
 · 
86 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: As endometriosis is known to be very painful in humans, therapeutic studies should consider pain-related aspects in experimental animals too. In a previous study, we found that common marmosets suffering from endometriosis show remarkable deviations in social behavior and cognitive tasks. METHODS: Female marmosets with endometriosis undergoing medical treatment were tested vs. two control groups (healthy and endometriosis monkeys without treatment) concerning behavioral aspects, cognitive skills, and mobility. RESULTS: The treated monkeys performed significant more social and self-grooming, comfort behavior and were more active than the untreated endometriosis monkeys. The treated marmosets even returned to equal levels as their healthy conspecifics. Cognitive and mobility tests revealed no significant differences. CONCLUSIONS: A beneficial effect of the applied endometriosis medication on behavioral impairments could be obtained. Including such measurements in therapeutic research contributes to aspects of animal welfare and pain-relieving potential of the tested compound.
    Journal of Medical Primatology 02/2013; DOI:10.1111/jmp.12042 · 0.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sulfated steroids function as a storage reservoir of biologically active steroid hormones. The sulfated steroids themselves are biologically inactive and only become active in vivo when they are converted into their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS are considered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast, prostate and endometrial cancer. The present review summarizes steroid derivatives as inhibitors of STS covering the literature from the early years of STS inhibitor development to October of 2012. A brief discussion of the function, structure and mechanism of STS and its role in estrogen receptor-positive (ER+) hormone-dependent breast cancer is also presented.
    The Journal of steroid biochemistry and molecular biology 02/2013; 137. DOI:10.1016/j.jsbmb.2013.01.013 · 3.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Steroid sulfatase (STS) is responsiblefor the conversion of estrone sulfate to estrone that can stimulate growth in endocrine-dependent tumors such as prostate cancer. Although STS is considered as a therapeutic target for the estrogen-dependent diseases, cellular function of STS are still not clear. Previously, we found that tumor necrosis factor (TNF)-α significantly enhances steroid sulfatase expression in PC-3 human prostate cancer cells through PI3K/Akt-dependent pathways. Here, we studied whether bacterial lipopolysaccharides (LPS) which are known to induce TNF-α may increase STS expression. Treatment with LPS in PC-3 cells induced STS mRNA and protein in concentration- and time-dependent manners. Using luciferase reporter assay, we found that LPS enhanced STS promoter activity. Moreover, STS expression induced by LPS increased PC-3 tumor cell migration determined by wound healing assay. We investigated that LPS induced IL-6 expression and IL-6 increased STS expression. Taken together, these data strongly suggest that LPS induces STS expression through IL-6 pathway in human prostate cancer cells.
    Biomolecules and Therapeutics 11/2012; 20(6):556-61. DOI:10.4062/biomolther.2012.20.6.556 · 0.84 Impact Factor
    This article is viewable in ResearchGate's enriched format