In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity

Shields-Botella, Jacqueline; Bonnet, Philippe; Duc, I.; Duranti, E; Cardinali, Simonetta; Prouheze, P; Chaigneau, A.M; Duranti, V.; Gribaudo, S; Rivière, Antoine; Mengual, Lourdes; Carniato, Denis; Cecchet, L; Lafay, J.; Rondot, B; Sandri, J; Pascal, J. C.; Delansorne, Remi

doi:10.1016/s0960-0760(03)00046-3

Cited by 12 publications

(14 citation statements)

References 21 publications

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“…As discussed in previous section, several coumarin derivatives have been reported to be steroid STS inhibitors and evaluated for breast cancer therapy [53,109]; however, clear evidence of AIs as antibreast cancer agent has not been demonstrated yet. Studies have shown benzopyranone substrates such as 4-benzyl-3-(4'-chlorophenyl)-7-methoxy-coumarin (41) to be a more potent competitive AI than several known AIs such as aminoglutethimide with respect to the androgen substrate.…”

Section: Aromatase Inhibitormentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

490

190

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The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.

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Section: Aromatase Inhibitormentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

490

190

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“…5 for structure), a prototype STS inhibitor; 99 this stimulated an intense search for non-estrogenic STS inhibitors. Various test systems have been used to test for estrogenicity of STS inhibitors: (i) binding to the isolated ER-a and -b; 100 (ii) stimulation of estrogen-dependent breast cancer cell growth 64,[101][102][103] ; (iii) induction of alkaline phosphatase in endometrial carcinoma cells; 69,104 (iv) stimulation of uterine weight in ovariectomized rats. 67,68,105,106 Furthermore, androgenicity of inhibitors was tested using an androgen-sensitive mammary carcinoma cell line.…”

Section: B Estrogenicity and Androgenicity Assaysmentioning

confidence: 99%

“…89,90 However, those experiments were done with the STS inhibitor EMATE, which is now known to be highly estrogenic; 104 thus, the pharmacological effects of this compound have to be evaluated with caution. In fact, other potent STS inhibitors, such as the chromenone sulfamates, 94 have been found to be inactive in a model of allergic contact dermatitis (J.G.…”

Section: P H a R M A C O L O G Y O F S T S I N H I B I T O R Smentioning

confidence: 99%

Steroid sulfatase inhibitors

Nußbaumer

Billich

2004

Medicinal Research Reviews

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Steroid sulfatase (STS) regulates the local production of estrogens and androgens from systemic precursors in several tissues. The enzyme catalyzes the hydrolysis of the sulfate esters of 3-hydroxy steroids, which are inactive transport or precursor forms of the active 3-hydroxy steroids. STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones. Therefore, they are considered as potential new therapeutic agents for the treatment of estrogen- and androgen-dependent disorders. Indications range from cancers of the breast, endometrium and prostate to androgenetic alopecia and acne. In this review, we give a comprehensive summary of the current knowledge and problems in the field of medicinal chemistry of STS inhibitors. The various types of inhibitors are presented and their structure-activity relationships are discussed. In addition to potent arylsulfamate-based, irreversible inhibitors, novel types of reversible inhibitors were recently discovered. The recent publication of the X-ray structure of STS will further boost research activities on this attractive target.

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“…EMATE had been identified as a potent STS inhibitor, but development of it as an anti-breast cancer agent was terminated since it was demonstrated to have estrogenic activity at least 5-fold that of ethynylestradiol when administered orally to rats [45]. Therefore, a number of recent reports have focused on sulfamate-type inhibitors devoid of estrogenic effects [46][47][48][49]. We confirmed in the cell-culture proliferation assay that no estrogenic effect was observed with KW-2581 itself.…”

Section: Discussionmentioning

confidence: 99%

A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models

Ishida

Nakata

Suzuki

et al. 2007

Breast Cancer Res Treat

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We screened a series of 17beta-(N-alkylcarbamoyl)-estra-1,3,5(10)trine-3-O-sulfamate derivatives, and describe here a potent and selective steroid sulfatase (STS) inhibitor with antitumor effects in breast cancer models in vitro and in vivo. In biochemical assays using crude enzymes isolated from recombinant Chinese hamster ovary cells expressing human arylsulfatses (ARSs), one of the best compounds, KW-2581, inhibited STS activity with an IC(50) of 4.0 nM, while > 1000-fold higher concentrations were required to inhibit the other ARSs. The failure to stimulate the growth of MCF-7 human breast cancer cells as well as in uteri in ovariectomized rats indicated the lack of estrogenicity of this compound. In MCF-7 cells transfected with the STS gene, termed MCS-2 cells, KW-2581 inhibited the growth of cells stimulated by estrone sulfate (E1S) but also 5-androstene-3beta, 17beta-diol 3-sulfate (ADIOLS) and dehydroepiandrostenedione 3-sulfate. We found that oral administration of KW-2581 inhibited both E1S- and ADIOLS-stimulated growth of MCS-2 cells in a mouse hollow fiber model. In a nitrosomethylurea-induced rat mammary tumor model, KW-2581 induced regression of E1S-stimulated tumor growth as effectively as tamoxifen or another STS inhibitor, 667 Coumate. Dose-response studies in the same rat model demonstrated that more than 90% inhibition of STS activity in tumors was necessary to induce tumor shrinkage. STS activity in tumors has well correlated with that in leukocytes, suggesting that STS activity in leukocytes could be used as an easily detectable pharmacodynamic marker. These findings demonstrate that KW-2581 is a candidate for development as a therapeutic agent for the treatment of hormone receptors-positive breast cancer.

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In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity

Cited by 12 publications

References 21 publications

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Steroid sulfatase inhibitors

A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models

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