Inhibition of steroid sulfatase activity and cell proliferation in ZR-75-1 and BT-474 human breast cancer cells by KW-2581 in vitro and in vivo.

Abstract

In the present study, we found that two hormone receptor-positive human breast cancer cell lines, ZR-75-1 and BT-474, naturally expressed steroid sulfatase (STS) protein and had catalytic activity to produce estrone from estrone sulfate (E1S) with a comparable level to those in human breast cancer tissues. E1S at physiological concentrations stimulated the growth of those cells. A novel steroidal STS inhibitor, KW-2581 inhibited the STS activity of ZR-75-1 cells with an IC(50) of 13 nM, a potency equal to or higher than that of the non-steroidal STS inhibitor, 667 COUMATE. The inhibitory effect of KW-2581 was enhanced by pre-incubation with STS enzyme, suggests being irreversible inhibition. KW-2581 inhibited the E1S-stimulated growth of ZR-75-1 cells with an IC(50) of 0.18 nM, but failed to inhibit the growth stimulated by 17beta-estradiol. Expression of E1S-induced progesterone receptors in ZR-75-1 cells was reduced by treatment of KW-2581 at concentrations as low as 0.1 nM. Oral administration of KW-2581 for 4 weeks caused tumor shrinkage in a mouse xenograft model. Tumor STS activity had been completely (>95%) eliminated by 24 hours after the last administration. These findings suggest that KW-2581 has considerable potential for therapeutic development as a novel anti-hormonal drug for treatment of breast cancer.

• Authors: Hiroyuki Ishida, Taisuke Nakata, Natsuko Sato, Pui-Kai Li, Takashi Kuwabara, Shiro Akinaga
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 104 Issue 2 Pg. 211-9 (Aug 2007) ISSN: 0167-6806 [Print] Netherlands
• PMID: 17061037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coumarins
• Enzyme Inhibitors
• KW 2581
• Receptors, Progesterone
• Sulfonamides
• Sulfonic Acids
• irosustat
• Estradiol
• Steryl-Sulfatase

Topics

• Animals
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Proliferation (drug effects)
• Coumarins (pharmacology)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Estradiol (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• In Vitro Techniques
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Receptors, Progesterone (metabolism)
• Signal Transduction (drug effects)
• Steryl-Sulfatase (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (chemical synthesis, chemistry, pharmacology)
• Sulfonic Acids
• Tumor Cells, Cultured