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Abstract: Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In this study, we used in vitro and in vivo assays to examine the inhibitory effects of oroxylin A, one of the main bioactive flavonoid extracted from Scutellaria radix, on the human breast carcinoma cell MDA-MB-231 invasion and migration. We found that oroxylin A can suppress cell adhesion, invasion and migration in a concentration-dependent manner. Moreover, oroxylin A led to the reduction of the activity and expression levels of MMP-2 and MMP-9 in gelatin zymography, real-time PCR and western blotting analysis. Further elucidation of the mechanism revealed that oroxylin A increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of MMP-2, and repressed the phorbol-12-myristate-13-acetate (PMA)-induced translocation of protein kinase Cδ (PKCδ), phosphorylation of extracellular signal-regulated kinase (ERK1/2) and binding activity of the transcription factor activator protein-1 (AP-1) which are upstream signaling molecules in MMP-9 expression. Our results also indicated that oroxylin A inhibited the lung metastasis of murine melanoma cell B16-F10 in vivo. Therefore, we proposed that oroxylin A might be developed as a therapeutic potential candidate for the treatment of cancer metastasis. [Copyright &y& Elsevier]

[Display omitted] Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high invasiveness, metastatic potential, and poor prognosis. Epithelial–mesenchymal transition (EMT) is pivotal in TNBC progression, becoming a promising target for TNBC treatment. Our study evaluated N-3, a novel synthetic bifendate derivative, which inhibited the EMT-associated migration and invasion of MDA-MB-231 and 4T1 TNBC cells. The results were consistent with the suppression of FOXC1 expression and transcriptional activity. Additional studies indicated that N-3 reduced the protein stability of FOXC1 by enhancing ubiquitination and degradation. Moreover, N-3 downregulated p-p38 expression and FOXC1 interaction, decreasing the stability of p38-regulated FOXC1. Further, N-3 blocked TNBC metastasis with an artificial lung metastasis model in vivo , related to FOXC1 suppression and EMT. These results highlight the potential of N-3 as a TNBC metastasis treatment. Therefore, FOXC1 regulation could be a novel targeted therapeutic strategy for TNBC metastasis. [ABSTRACT FROM AUTHOR]

As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the MDR reversal results indicated that compounds 6k and 9c might be promising leads for developing novel anti-cancer agents with P-gp and tumor metastasis inhibitory activities. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that inflammatory microenvironment facilitates tumor metastasis. Here, we found that LFG-500, a novel synthetic flavonoid, significantly inhibited epithelial-mesenchymal transition (EMT) in human lung adenocarcinoma A549 and H1299 cells co-cultured with LPS-challenged THP-1 cells or cultured in THP-1 cell-derived conditioned medium. Moreover, we found that TNF-α is a direct and decisive factor for promoting EMT and LFG-500 suppressed TNF-α-induced EMT and cell motility. NLRP3 knockdown inactivated NLRP3 inflammasome, which subsequently inhibited EMT and blocked cell migration, indicating that TNF-α-induced EMT requires the NLRP3 inflammasome. LFG-500 inhibited the activation of the NLRP3 inflammasome, thus inhibiting EMT. Moreover, LFG-500 treatment significantly inhibited metastasis in vivo by downregulating NLRP3 expression. Importantly, we found that NLRP3 was highly expressed in high-grade lung adenocarcinoma and that its expression was correlated with lymph node metastasis. NLRP3 and vimentin levels were significantly increased in matched metastatic lymph nodes. Moreover, a significant positive correlation was observed between their levels. Together, these results suggest that LFG-500 markedly suppresses EMT by inhibiting the NLRP3 inflammasome in the inflammatory microenvironment and that NLRP3 is a potential biomarker of lung adenocarcinoma metastasis. [ABSTRACT FROM AUTHOR]