Breast cancer has become the most common cancer among women worldwide. Among breast cancers, metastatic breast cancer is associated with the highest mortality rate. Twist1, one of the epithelial-mesenchymal transition-regulating transcription factors, is known to promote the intravasation of breast cancer cells into metastatic sites. Therefore, targeting Twist1 to develop anti-cancer drugs might be a valuable strategy. In this study, LY-290181 dose-dependently inhibited migration, invasion, and multicellular tumor spheroid invasion in breast cancer cell lines. These anti-cancer effects of LY-290181 were mediated through the down-regulation of Twist1 protein levels. LY-290181 inhibited extracellular signal-regulated kinase and c-Jun N-terminal kinase signaling pathways. Therefore, our findings suggest that LY-290181 may serve as a basis for future research and development of an anti-cancer agent targeting metastatic cancers. [BMB Reports 2023; 56(7): 410-415].

2019-02-01·European journal of medicinal chemistry1区 · 医学

New naphthopyran analogues of LY290181 as potential tumor vascular-disrupting agents

1区 · 医学

Article

作者: Biersack, Bernhard ; Schmitt, Florian ; Andronache, Ion ; Gold, Madeleine ; Rothemund, Matthias ; Schobert, Rainer ; Mueller, Thomas

A series of 19 analogues of the antiproliferative naphthopyran LY290181 were prepared for structure-activity relationship studies. We found the best activities for test compounds bearing small substituents at the meta position of the phenyl ring. The mode of action of LY290181 and eight new analogues was studied in detail. The compounds were highly anti-proliferative with IC₅₀ values in the sub-nanomolar to triple-digit nanomolar range. The new analogues led to G2/M arrest due to interruption of the microtubule dynamics. In 518A2 melanoma cells they caused a mitotic catastrophe which eventually led to apoptosis. The naphthopyrans also induced a disruption of the vasculature in the chorioallantoic membrane (CAM) of fertilized chicken eggs as well as in xenograft tumors in mice. In a preliminary therapy trial, the difluoro derivative 2b retarded the growth of resistant xenograft tumors in mice.

1998-06-01·Medical hypotheses4区 · 医学

Polyphenol-mediated inhibition of AP-1 transactivating activity may slow cancer growth by impeding angiogenesis and tumor invasiveness

4区 · 医学

Article

作者: McCarty, M F

Certain polyphenols, capable of activating transcription via antioxidant response elements, potently induce Fra-1/Fra-2, thereby antagonizing the transactivating activity of AP-1 complexes. Since AP-1 is crucial to the induction of matrix proteases required for angiogenesis and tumor invasion, it is reasonable to suspect that adequate intakes of appropriate polyphenols would have utility in cancer therapy. Indeed, green tea polyphenols have reduced tumor growth rate and/or metastatic capacity in several animal studies. Additional measures for down-regulating AP-1 activity may include fish oil, heparin, and the drug LY290181. Down-regulation of AP-1 activity as a general therapeutic strategy merits further consideration.

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