wortmannin and Breast-Neoplasms

Topics: Antineoplastic Agents; Apoptosis; Azetidines; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crystallography, X-Ray; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Molecular Structure

The invasive behavior of cancer cells resulting in metastasis is the major cause of cancer-related deaths. Rhapontigenin (1) has various biological activities including anticancer activities. However, whether and how 1 affects cancer invasion has never been explored. Here, we examined the anti-invasive effects of 1 and its underlying molecular mechanisms in the highly invasive human breast cancer cell line designated MDA-MB-231. At noncytotoxic concentrations, 1 strongly suppressed serum-induced cell migration and invasion as judged by Boyden chamber analysis and wound-healing assays, respectively. Compound 1 strikingly reduced Rac1 activity as judged by both absorbance-based and pull-down assays. In addition, its downstream effectors such as WASP-family verprolin homologous proteins 2 (WAVE-2) and p21-activated kinase 1 (PAK1) signaling cascades were attenuated after treatment with 1. Immunofluorescence staining showed that 1 diminished lamellipodia formation at the leading edge of cells. Finally, 1 decreased the phosphorylation of phosphoinisitide-3-kinase (PI3K) and AKT. Rac1 activity was inhibited by the PI3K inhibitor wortmannin. Taken together, these results suggest that 1 suppresses breast cancer cell migration and invasion, which is involved in inhibiting the PI3K-dependent Rac1 signaling pathway.

Topics: Androstadienes; Breast Neoplasms; Cell Movement; Female; Humans; Molecular Structure; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes; Wnt Signaling Pathway; Wortmannin

Naturally occurring furanosteroids such as viridin and wortmannin have long been known as potent inhibitors of the lipid kinase PI-3K. We have been interested in directly accessing analogs of these complex natural products from abundant steroid feedstock materials. In this communication, we describe the synthesis of viridin/wortmannin hybrid molecules from readily available building blocks that function as PI-3K inhibitors and maintain their electrophilic properties. The compounds also show anti-proliferative effects against a breast cancer line.

Topics: Androstadienes; Androstenes; Bacteriocins; Binding Sites; Breast Neoplasms; Cell Survival; Crystallography, X-Ray; Female; Humans; MCF-7 Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Structure, Tertiary; Steroids; Wortmannin