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

Amira A Abdellatef; Yue Zhou; Akane Yamada; Sahar A Elmekkawy; Aki Kohyama; Satoru Yokoyama; Meselhy R Meselhy; Yuji Matsuya; Hiroaki Sakurai; Yoshihiro Hayakawa

doi:10.1016/j.biopha.2021.111737

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

Biomed Pharmacother. 2021 Aug:140:111737. doi: 10.1016/j.biopha.2021.111737. Epub 2021 May 18.

Authors

Affiliations

¹ Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
² Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
³ Department of Chemistry of Natural Compounds, National Research Centre, Egypt.
⁴ Department of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
⁵ Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
⁶ Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, Japan. Electronic address: [email protected].

PMID: 34020249
DOI: 10.1016/j.biopha.2021.111737

Abstract

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-κB activation induced by TNF-α. GSD-1 prevented the nuclear translocation of p65 through the blockade of IκBα degradation and p65 phosphorylation, and further inhibited the activation of upstream kinases, including transforming growth factor-β activated kinase 1 (TAK1), IκB kinase (IKK) α, and IKKβ. Furthermore, GSD-1 inhibited the cell-intrinsic activation of NF-κB, 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-κB activation that has potential for treating breast cancer growth and metastasis.

Keywords: Anti-cancer; Breast cancer; Guggulsterone; Inflammatory signal; Metastasis; NF-κB.

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / pathology
Cell Line, Tumor
Humans
Mice
NF-kappa B / antagonists & inhibitors*
Pregnenediones / pharmacology*
Signal Transduction / drug effects
Tumor Necrosis Factor-alpha / pharmacology
Wound Healing / drug effects

Substances

Antineoplastic Agents
NF-kappa B
Pregnenediones
Tumor Necrosis Factor-alpha