Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Abstract

Background: Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic.Methods: We explored the ability of active compounds derived from natural herbs to inhibit TNBC metastasis using the methods of molecular biology, cell biology, protein chemistry, pharmacology, and xenografted mice.Results: Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2).Conclusions: Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.

Male contraceptive development: A medicinal chemistry perspective

“…Target identification studies using mice treated with triptonide, mouse testes lysate and a drug affinity responsive target stability (DARTS) assay, [41] demonstrated that triptonide in mice was acting as a protein-protein interaction inhibitor through binding to junction plakoglobin and disrupting its interactions with the Spermatid Maturation 1 (SPEM1) protein, during spermiogenesis. However, triptonide has also been highlighted as a potential anti-cancer agent, which inhibits several other proteins and pathways, [42][43][44] suggesting that triptonide can bind to multiple protein targets in the host. Triptonide displays chemically reactive and metabolically labile functional groups, including a ketone and a number of epoxides, which are moieties that are typically avoided in drug design, to avoid potential toxicity.…”