title: A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer.
abstract: Endocrine therapy is the ideal treatment choice for estrogen receptor alpha (ERalpha)-positive breast cancer patients. Principal used therapies target either the ERalpha e.g. by selective ERalpha modulators (SERMs) such as tamoxifen or target estrogen biosynthesis with aromatase inhibitors. Steroid sulfatase (STS) plays a crucial role in formation of compounds with estrogenic properties, converting inactive sulfate-conjugated steroids to active non-conjugated forms. Steroid sulfates are considered as a reservoir for active steroids due to their prolonged half-life and increased concentration in plasma. STS is present in several tissues including the breast, and the STS the mRNA level and enzyme activity is significantly increased in ERalpha-positive breast tumors. Inhibition of STS is therefore a new approach for decreasing estrogenic steroids that stimulate breast cancer. The novel dual-acting compound SR 16157 is designed as a sulfamate-containing STS inhibitor that releases a tissue-selective SERM SR 16137. Use of a dual-target STS inhibitor and SERM represents a new strategy in the treatment of hormone-dependent breast cancer. In this study, we tested the potential of SR 16157 and SR 16137 on STS activity, cell growth and ERalpha function in MCF-7 breast cancer cells. We confirmed that the dual-target compound SR 16157 exerts STS inhibition and antiestrogenic effects. SR 16157 was a highly effective growth inhibitor, being 10 times more potent than the antiestrogens SR 16137 and tamoxifen. Relative to tamoxifen, SR 16137 displays profoundly improved ERalpha binding affinity and antiestrogenic effects on expression of estrogen-regulated genes. Thus, the dual-target SR 16157 is possibly a promising new treatment alternative, superior to tamoxifen.
authors.affiliation: Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen, Denmark.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Rasmussen
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.forename: Richard H
authors.initials: RH
authors.lastname: Peters
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
mesh_terms: D001667:Binding, Competitive; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D008024:Ligands; D009651:Norpregnatrienes / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C526897:21-(2-N,N-diethylaminoethyl)oxy-7-methyl-19-norpregna-1,3,5(10)-triene-3-O-sulfamate; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D008024:Ligands; D009651:Norpregnatrienes; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D043266:Steryl-Sulfatase