ABSTRACT
Matrix metalloproteinase 9 (MMP9), an MMP isozyme, plays a crucial role in tumor progression by degrading basement membranes. It has therefore been proposed that the pharmacological inhibition of MMP9 expression or activity could inhibit tumor metastasis. We previously isolated two novel methoxylated flavones, casedulones A and B, from the leaves and/or roots of Casimiroa edulis La Llave and determined that these casedulones have antitumor activity that acts via the reduction of MMP9. Here, we examined how these casedulones suppress lipopolysaccharide (LPS)-induced MMP9 expression in human monocytic THP-1 cells. The casedulones suppressed the LPS-induced signal transducer and activator of transcription 3 (STAT3) pathway, which participates in MMP9 induction. In addition, AG490 and S3I-201, inhibitors of Janus kinase (JAK) and STAT3, suppressed LPS-mediated MMP9 induction, suggesting that the casedulones suppressed MMP9 induction through the inhibition of JAK/STAT3 pathways. Based on the findings that cycloheximide, an inhibitor of de novo protein synthesis, completely inhibited LPS-mediated MMP9 induction, the role of de novo proteins in MMP9 induction was further investigated. We found that the casedulones inhibited the induction of interleukin-6 (IL-6), a key inflammatory cytokine that participates in STAT3 activation. Moreover, tumor necrosis factor-α (TNFα)-mediated MMP9 induction was significantly suppressed in the presence of the casedulones. Taken together, these findings suggest that casedulones inhibit the IL-6/STAT3 and TNFα pathways, which all involve LPS-mediated MMP9 induction.
Subject(s)
Flavones , Janus Kinases , Matrix Metalloproteinase 9 , Plant Extracts , STAT3 Transcription Factor , Signal Transduction , Tumor Necrosis Factor-alpha , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Humans , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 9/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Plant Extracts/pharmacology , Plant Extracts/chemistry , Flavones/pharmacology , Flavones/chemistry , Janus Kinases/metabolism , Janus Kinases/genetics , Signal Transduction/drug effectsABSTRACT
Casimiroa edulis La Llave is known to contain unusual 5,6-dimethoxyflavones bearing a variously oxygenated B-ring. Phytochemical investigation of the leaves and the roots of C. edulis achieved the isolation of two new methoxylated flavones, named casedulones A (1) and B (2), together with 12 known analogues. Their unique structures were established with the aid of spectral analyses and total syntheses. Pre-treatment with 20 µM of 1 and 2 suppressed MMP-9 expression in LPS-mediated THP-1 cells, indicating that the characteristic flavonoids in C. edulis could be potential anti-angiogenics for cancer prevention.
