title: A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models.
abstract: 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.
authors.affiliation: Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd, 1188 Shimotogari, Sunto-gun, Nagaizumi-cho, Shizuoka 4118731, Japan. hiroyuki.ishida@kyowa.co.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishida
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakata
authors.forename: Masayo
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Natsuko
authors.initials: N
authors.lastname: Sato
authors.forename: Yoko
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Miho
authors.initials: M
authors.lastname: Takebayashi
authors.forename: Hideharu
authors.initials: H
authors.lastname: Anazawa
authors.forename: Chikara
authors.initials: C
authors.lastname: Murakata
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D003374:Coumarins / Q000494:pharmacology; D006224:Cricetinae; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008770:Methylnitrosourea / Q000633:toxicity; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013451:Sulfonic Acids; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; C524251:KW 2581; D011980:Receptors, Progesterone; D013449:Sulfonamides; D013451:Sulfonic Acids; D013629:Tamoxifen; D004970:Estrone; C520511:irosustat; D004958:Estradiol; D008770:Methylnitrosourea; D043266:Steryl-Sulfatase; C017296:estrone sulfate