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.

Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

“…Therefore, this compound may be effective at inhibiting both estrogen and androgen stimulated carcinomas. Further studies by the same group demonstrated that KW-2581 was able to inhibit the growth of the hormone receptor-positive human breast cancer cell lines ZR-75-1 and BT-474 (Ishida et al 2007b). …”

A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models

“…1) inhibits STS activity, E1S-stimulated cell proliferation and tumor growth using human breast cancer models [34]. In the present report, we describe the selective inhibition by KW-2581 against STS among ARSs, its estrogenic effects, inhibitory effects on estrogen-dependent growth of breast cancers in vitro and in vivo, and PK/PD relationships in a preclinical model.…”

“…KW-2581 inhibits 3-sulfate steroid-stimulated cell proliferation, but does not inhibit 3-hydoxy steroid-stimulated cell proliferation MCF-7 cells are both ER and PgR positive breast cancer cells, and highly sensitive to estrogens, but insensitive to sulfated estrogens because of their low endogenous STS level [34,41]. We therefore generated human STS gene-transfected MCF-7 cells (termed MCS-2 cells) to establish a model system for evaluation of STS inhibitors and determined the effects of STS inhibitors on hormone-dependent cell proliferation.…”

Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

“…In parallel to the development of the 667 COUMATE 2, scientists from Kyowa Hakko Kogyo Co. Ltd reported a series of 17beta-(N-alkylcarbamoyl)-estra-1,3,5(10)trine-3-O-sulfamate derivatives as potent and selective STS inhibitors [12]. Among them, the compound KW-2581 (5) inhibited the STS activity with an IC 50 of 4.0 nM when evaluated on the crude enzymes isolated from recombinant Chinese hamster ovary cells, which express the human arylsulfatases (ARSs) and are very promising therapeutic targets for clinical trials [13].…”