Evaluation of synthetic isoflavones on cell proliferation, estrogen receptor binding affinity, and apoptosis in human breast cancer cells

Abstract

Natural isoflavones have demonstrated numerous pharmacological activities in breast cancer cells, including antiproliferative activities and binding affinities for estrogen receptors (ERs). Chemical modifications on the isoflavone ring system have been prepared and explored for the development of new therapeutics for hormone-dependent breast cancer. The antiproliferative actions of the synthesized isoflavones on MCF-7 and MDA-MB-231 breast cancer cells were examined, as well as cytotoxicity, interaction with estrogen receptors, and proapoptotic activity. The compounds were screened in the absence and in the presence of estradiol to evaluate whether or not estradiol could rescue cell proliferation on MCF-7 cells. Several compounds were able to inhibit cell proliferation in a dose-dependent manner, and compounds containing the bulky 7-phenylmethoxy substituent resulted in cell toxicity not only in MCF-7 cells but also in MDA-MB-231 cells. Selected synthetic isoflavones were able to bind to estrogen receptor with low affinity. Apoptotic pathways were also activated by these compounds in breast cancer cells. The majority of the compounds can bind to both ERs with low affinity, and their effects on hormone-independent breast cancer cells suggest that their ability to inhibit cell growth in breast cancer cells is not exclusively mediated by ERs. Thus, the synthetic trisubstituted isoflavones act on multiple signaling pathways leading to activation of mechanisms of cell-death and ultimately affecting breast cancer cell survival.

A New Nonestrogenic Steroidal Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

“…To determine the potential antiestrogenic activity of inhibitor PBRM, the T-47D (ER ERa binding assay. A competitive binding assay using a purified full-length recombinant human ERa (Life Technologies) was done as previously described (34,35). Briefly, each reaction consisted of 1.2 nmol/L rhERa and 2.5 nmol/L [ 3 H]-estradiol in assay buffer (10 mmol/L Tris, 1.5 mmol/L EDTA, 1 mmol/L dithiothreitol, 10% glycerol, 1 mg/mL bovine serum albumin, pH 7.5) with different concentrations of the inhibitors or untritiated estradiol (E2) in a total reaction volume of 100 mL.…”

In vitro evaluation of a tetrahydroisoquinoline derivative as a steroid sulfatase inhibitor and a selective estrogen receptor modulator

“…ERα binding assay A competitive binding assay using a purified full-length recombinant human ERα (Life Technologies, Grand Island, NY) was done as previously described [17,18].…”

Soy and Soy-Based Foods: Role in Health and Nutrition

“…Isoflavones have attracted a great deal of attention due to their antioxidant (Kao and Chen 2006;Chung et al 2008), antiinflammatory García-Lafuente et al 2009), and antiallergic (Chang et al 2000) properties. These compounds have shown to reduce the risk of cardiovascular disease (Jackman et al 2007), and promote the inhibition of cancer cell growth (Sarkar and Li 2003;Kao et al 2007;Davis et al 2008). Furthermore, soy intake plays an important role in the prevention of several ailments including osteoporosis, and menopausal symptoms (Dijsselbloem et al 2004;Phrakonkham et al 2007;Coxam 2008;Ma et al 2008) since the isoflavones act as antiestrogens (Okamoto et al 2006;Zhang et al 2007) and tyrosine protein kinase inhibitors (Papazisis et al 2006).…”