Inhibition of placental estrone sulfatase activity and MCF-7 breast cancer cell proliferation by estrone-3-amino derivatives

Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than in plasma, presumably due to in situ formation of estrogen. Several Lines of evidence indicate that the major source of estrogen in breast cancer cells may be from conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Inhibitors of estrone sulfatase may thus be potential agents for the treatment of estrogen-dependent breast cancer. We designed and synthesized a series of estrone-3-amino derivatives as potential estrone sulfatase inhibitors. We tested the inhibitory potential of these compounds using human placental microsomes, which contain a substantial amount of estrone sulfatase activity. Several compounds in the series significantly inhibited estrone sulfatase activity of the human placental microsomes when present at 10 mu M. The IC50 for the estrone-3-amino compounds ranged from 8.7 to 14.6 mu M. We next tested the ability of the estrone-3-amino derivatives to inhibit growth of the estrogen-dependent MCF-7 breast cancer cell line. MCF-7 cells showed substantial proliferation in the presence of 100 nM estrone sulfate in estrogen-free media, indicating that the cells were capable of converting estrone sulfate into estrone. The proliferative effect of estrone sulfate (1 mu M) was significantly blocked by the estrone-3-amino derivatives at 10 mu M. The magnitude of MCF-7 cell inhibition resulting from treatment with the estrone-3 amino compounds was similar to or exceeded that of Danazol, but was less than the level resulting from treatment with estrone sulfamate. Using data from all of the compounds tested, inhibition of MCF-7 cell proliferation was positively correlated with inhibition of placental estrone sulfatase activity, suggesting that the reduction in cell growth was attributable to the blockade of sulfatase activity. In support of this, there was no relationship between inhibition of estrone sulfatase activity and inhibition of cell growth when the estrogen-independent cell line MDA-MB-231 was used. Our results indicate the possible utility of estrone-3-amino derivatives for inhibition of estrone sulfatase activity. Further, our data support the concept that estrone sulfatase inhibitors may be useful as therapeutic agents for estrogen-dependent breast cancers. Copyright (C) 1996 Elesevier Science Ltd.