Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells

A84

Estrogen and estrogen receptor (ER)-mediated signaling are crucial in the etiology and progression of human breast cancer. Attenuating ER activities by natural products can be a potential strategy to decrease breast cancer risk. We have recently discovered that the pyranocoumarin compound decursin and its isomer decursinol angelate (DA) from the dried root of Korean medicinal herb Angelica gigas Nakai (AGN) have potent novel anti-androgen receptor (AR) signaling activities. Because ER and AR belong to the steroid receptor super-family, we determined whether these pyranocoumarin compounds affected ER expression and signaling in breast cancer cells. We treated estrogen dependent MCF-7 and estrogen-independent MDA MB-231 human breast cancer cells in cell culture with decursin and DA and examined cell growth, apoptosis, ERα and ERβ expression and estrogen-stimulated signaling. We compared these compounds with the pyranocoumarin core decursinol to examine possible structure-activity relationship. Decursin and DA exerted strong growth inhibitory effects on MCF-7 cells in the presence or absence of estrogen stimulation through G₁ arrest and caspase-mediated apoptosis. They decreased ERα in MCF-7 cells at both mRNA and protein levels and suppressed the expression of an estrogen-stimulated gene pS2 and the trans-activation of an estrogen response element-reporter. These compounds also induced arrest in G₁ as well as G₂ and apoptosis of MDA MB-231 cells, accompanied by an increased expression of ERβ. In contrast, decursinol, which lacks the side chain of decursin and DA, did not have these cellular and molecular activities at comparable concentrations. Furthermore, decursin enhanced the growth inhibitory effect of a pure anti-estrogen Faslodex in MCF-7 cells. The side chain of decursin and DA is crucial for their anti-ER signaling and breast cancer growth inhibitory activities as is for the anti-AR signaling effects in prostate cancer cells. These data provide mechanistic rationales for validating the chemopreventive efficacy of decursin and its derivatives in preclinical animal models of breast cancer.