Anti-metastatic function of triterpene phytochemicals from guggul by targeting tumor-intrinsic NF-kB activation in triple-negative breast cancer cells

Abstract

Background: The endogenous activity of NF-κB is often elevated in various types of cancer cells, particularly breast cancer, and is strongly correlated with the induction of target genes that can inhibit apoptosis, interact with cell-cycle regulation, promote cell invasion and contribute to tumorigenesis, inflammation, and metastatic growth as well as drug resistance. Thus, the downregulation of NF-κB is regarded as a promising therapeutic target to inhibit breast cancer growth and metastasis. Purpose: Since no NF-κB inhibitor has yet been approved by the FDA, we aim to identify small molecules from natural resources that could potentially inhibit NF-κB and suppress breast cancer metastasis. Study design: In the current study, nineteen extracts from different valuable medicinal plants were screened for their prospective biological activity against NF-κB transcriptional activation in 4T1 breast cancer cells, followed by isolation and purification analysis of the major active compounds from guggul extract, as it exhibited the most inhibitory efficacy of NF-κB activation. Results: A bioassay-guided isolation of active constituents from the promising candidate, guggul methanol extract (GU-M), using NF-κB reporter gene assay was performed to identify potential anti-metastatic agents for triple-negative breast cancer cells (TNBC) and resulted in the isolation of four known major compounds namely; guggulsterone M (1), guggulsterol Ι (2), myyrhanol A (3), and myyrhanone A (4). Conclusion: Among the isolated compounds, myrrhanol A and myrrhanone A at the concentration of 10 μM markedly inhibited the intrinsic NF-κB pathway and potently suppressed the proliferative and metastatic abilities of murine and human breast cancer cells; 4T1, MDA-MB-231, and MDA-MB-453.

Keywords

• Commiphora wightii
• Guggul
• Triterpenes
• NF-κB
• Breast cancer
• Metastasis