Synthetic Demethylwedelolactones Derivatives Inhibit Invasive Growth of Mda-Mb-231 Breast Cancer Cells In Vitro and In Vivo

Abstract

Combretastatins, which are an important group of anticancer drugs,were isolated by Pettit et al. from the African tree Combretum caffrum in 1989. Additionally, Liang et al. have reported that ten coumestans were isolated fromthe roots of Hedysarum multijugum, which is a plant in Hedysarum Linn. of the family Leguminosae used as a folk herbal drug in northwest China. Coumestans comprise a class of naturally occurring products with a variety of biological activities including phytoestrogenic, antibacterial, antifungal, antimyotoxic, and phytoalexine effects. The anticancer properties of demethylwedelolactone (DWEL) and wedelolactone (WEL), which are naturally occurring coumestans, have not been well characterized. Due to their biological activities, the synthesis of DWEL is achieved in which the longest linear sequence is only eight steps in 38% overall yield from commercially available phloroglucinol. Furthmore, the molecular model was examined the interactions of proteins and ligands as well. Finally, in this study, we investigated the anti-invasive effects of synthetic WEL and DWEL on human MDA-MB-231 breast cancer cells. We found that WEL and DWEL inhibited the anchorage-independent growth and also suppressed cell motility and cell invasion of MDA-MB-231 cells. In addition, WEL and DWEL reduced the activity and expression of matrix metalloproteinases (MMPs) involved in blocking the IκB-α/NFκB and MEK/ERK signaling pathways in MDA-MB-231 cells. Furthermore, DWEL suppressed the metastasis and lung colonization of the tumor cells in the nude mice. Altogether, these data suggest that DWEL derivatives exert anti-invasive growth effect on breast cancer cells.