Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors

J Steroid Biochem Mol Biol. Jul-Aug 2000;73(5):225-35. doi: 10.1016/s0960-0760(00)00077-7.

Abstract

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.

MeSH terms

  • Arylsulfatases / antagonists & inhibitors*
  • Breast Neoplasms
  • Cell Division / drug effects*
  • Dehydroepiandrosterone Sulfate / antagonists & inhibitors
  • Dehydroepiandrosterone Sulfate / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Estrone / analogs & derivatives*
  • Estrone / antagonists & inhibitors
  • Estrone / pharmacology*
  • Female
  • Humans
  • Indicators and Reagents
  • Kinetics
  • Molecular Structure
  • Steryl-Sulfatase
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Indicators and Reagents
  • Sulfonamides
  • Estrone
  • Dehydroepiandrosterone Sulfate
  • Arylsulfatases
  • Steryl-Sulfatase
  • estrone sulfate