Synthetic E-guggulsterone derivative GSD-1 inhibits NF-κB signaling and suppresses the metastatic potential of breast cancer cells

Guggulsterone (GS) [4,17(20)-pregnadiene-3,16-dione], is the main active phytosterol constituent in guggul, the gum resin of Commiphora wightii (Arnott.) Bhand./Commiphora mukul Engl. tree, and is known for its medicinal effects. In this study, we report that GSD-1, a structurally-related synthetic GS derivative, strongly inhibits NF-kappa B activation induced by TNF-alpha. GSD-1 prevented the nuclear translocation of p65 through the blockade of I kappa B alpha degradation and p65 phosphorylation, and further inhibited the activation of upstream kinases, including transforming growth factor-beta activated kinase 1 (TAK1), I kappa B kinase (IKK) alpha, and IKK beta. Furthermore, GSD-1 inhibited the cell-intrinsic activation of NF-kappa B, and exerted its direct anti-cancer and anti-metastatic effects in both murine and human breast cancer cell lines. This study demonstrated GSD-1 to be an attractive compound to target NF-kappa B activation that has potential for treating breast cancer growth and metastasis.

Automated summary

The synthetic derivative GSD-1 strongly inhibits NF-kappa B activation, preventing nuclear translocation and cell-intrinsic activation, showing potential for treating breast cancer growth and metastasis.