Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors.
Steroid sulfatase (STS) regulates the formation of active steroids from systemic precursors, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS). In breast tissues, this pathway is a source for local production of estrogens, which support the growth of endocrine-dependent tumours. Therefore, inhibitors of STS could have therapeutic potential. In this study, we report on substituted chromenone sulfamates as a novel class of non-steroidal irreversible inhibitors of STS. The compounds are substantially more potent (6- to 80-fold) than previously described types of non-steroidal inhibitors when tested against purified STS. In MCF-7 breast cancer cells, they inhibit STS activity with IC(50) below 100 pM. Importantly, the compounds also potently block estrone sulfate-stimulated growth of MCF-7 cells, again with IC(50) below 100 pM. For one compound, we also observed a lack of any estrogenic effect at high concentrations (1 microM). We also demonstrate for the first time that STS inhibitors can block the DHEAS-stimulated growth of MCF-7 cells. Interestingly, this cannot be achieved with specific inhibitors of the aromatase, suggesting that stimulation of MCF-7 cell growth by DHEAS follows an aromatase-independent pathway. This gives further justification to consider steroid sulfatase inhibitors as potential drugs in the therapy of breast cancer.
Billich
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A
Novartis Research Institute Vienna, Brunnerstrasse 59, A-1235, Wien, Austria. andreas.billich@pharma.novartis.com
Nussbaumer
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P
Lehr
P
P
D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects*; D019314:Dehydroepiandrosterone Sulfate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D043266:Steryl-Sulfatase; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D013449:Sulfonamides; D004970:Estrone; D019314:Dehydroepiandrosterone Sulfate; D001192:Arylsulfatases; D043266:Steryl-Sulfatase; C017296:estrone sulfate