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

Cheng Jiang,Eun-Ok Lee,Hyo-Jung Lee,Junming Guo,Sung-Hoon Kim,Bingxiu Xiao,Junxuan Lu,Zhe Wang

doi:10.1186/bcr1790

Abstract

IntroductionEstrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer. Attenuating ER activities by natural products is a promising strategy to decrease breast cancer risk. We recently discovered that the pyranocoumarin compound decursin and its isomer decursinol angelate (DA) have potent novel antiandrogen receptor signaling activities. Because the ER and the androgen receptor belong to the steroid receptor superfamily, we examined whether these compounds affected ER expression and signaling in breast cancer cells.MethodsWe treated estrogen-dependent MCF-7 and estrogen-independent MDA MB-231 human breast cancer cells with decursin and DA, and examined cell growth, apoptosis, and ERα and ERβ expression in both cell lines – and, in particular, estrogen-stimulated signaling in the MCF-7 cells. We compared these compounds with decursinol to determine their structure-activity relationship.ResultsDecursin and DA exerted growth inhibitory effects on MCF-7 cells through G1 arrest and caspase-mediated apoptosis. These compounds decreased ERα in MCF-7 cells at both mRNA and protein levels, and suppressed estrogen-stimulated genes. Decursin and the pure antiestrogen Faslodex™ exerted an additive growth inhibitory effect on MCF-7 cells. In MDA MB-231 cells, these compounds induced cell-cycle arrests in the G1 and G2 phases as well as inducing apoptosis, 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.ConclusionThe side chain of decursin and DA is crucial for their anti-ER signaling and breast cancer growth inhibitory activities. These data provide mechanistic rationales for validating the chemopreventive and therapeutic efficacy of decursin and its derivatives in preclinical animal models of breast cancer.

Highlights

Estrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer
The side chain of decursin and decursinol angelate (DA) is crucial for their anti-ER signaling and breast cancer growth inhibitory activities
Requirement of side chain for cell-cycle arrest and apoptosis induction in estrogen-dependent and estrogen-independent breast cancer cells To examine whether an induction of cell-cycle arrest and apoptosis contributed to the inhibition of breast cancer cell growth by decursin, and to determine the chemical structure requirement for such activities, we evaluated the effects of decursin and of its structural isomer DA versus decursinol in complete medium on the cell-cycle distribution and apoptosis in MCF-7 cells (Figure 2) and in MDA-MB231 estrogen-independent breast cancer cells (Figure 3)

Summary

Introduction

Estrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer. Breast cancer is the most commonly diagnosed nonskin malignancy among American women, accounting for approximately 32% (211,000 cases) of all new cancer cases per year [1]. It is the second leading cause of cancer death in US women, claiming the lives of 41,000 annually. Novel agents that target ERα signaling as well as estrogen production without agonist activities will be desirable for breast cancer chemoprevention and treatment, and for women who have finished the prescribed course of tamoxifen [12,13,14,15]

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Conclusion