A Flavonoid Glycoside Compound from Murraya paniculata (L.) Interrupts Metastatic Characteristics of A549 Cells by Regulating STAT3/NF-κB/COX-2 and EGFR Signaling Pathways.

Metastasis remains the leading cause of death from lung carcinoma. It is urgent to find safe and efficient pre-metastasis preventive agents for cancer survivors. We isolated a flavonoid glycoside, hexamethoxy flavanone-o-[rhamnopyranosyl-(1 â†’ 4)-rhamnopyranoside (HMFRR), from the traditional Chinese medicine (TCM) Murraya paniculata (L.) that can effectively inhibit the adhesion, migration, and invasion of lung adenocarcinoma A549 cells in vitro. Molecular and cellular studies demonstrated that HMFRR significantly downregulated the expressions of cell adhesion-related and invasion-related molecules such as integrin ß1, EGFR, COX-2, MMP-2, and MMP-9 proteins. Additionally, HMFRR effectively downregulated the expressions of epithelial-mesenchymal transition (EMT) markers (N-cadherin and vimentin) and upregulated that of E-cadherin. Moreover, these inhibitions were mediated by interrupting STAT3/NF-κB/COX-2 and EGFR/PI3K/AKT signaling pathways. Furthermore, HMFRR counteracted the expressions of cell adhesion molecules (ICAM-1, VCAM-1, and E-selectin) stimulated by interleukin-1ß in human pulmonary microvascular endothelial cells (HPMECs). As a result, HMFRR interrupted the adhesion of A549 cells to HPMECs. Collectively, these results indicate that HMFRR may become a good candidate for cancer metastatic chemopreventive agents by interrupting the STAT3/NF-κB/COX-2 and EGFR signaling pathways.

The paradigm-shifting idea and its practice: from traditional abortion Chinese medicine Murraya paniculata to safe and effective cancer metastatic chemopreventives.

Recent large epidemiological studies demonstrated benefit of oral contraceptives in reducing cancer risk, and our analysis also showed molecular and cellular similarities between embryo implantation and CTCs adhesion-invasion to endothelium. We here hypothesize that abortion traditional Chinese medicine (TCM) may serve well for pre-metastatic chemoprevention. To test the hypothesis, we selected the safe and well-known abortifacient TCM Murraya paniculata and identified a most-promising extracted fraction G (containing flavonoids and coumarins) from its many raw ethanol/dichloromethane extracts by using the bioactivity-guided fast screen assay. G showed free radical scavenging effect, and specifically inhibited both embryo implantation to human endometrial bed and cancer HT29 cells to human endothelium in a concentration-dependent manner (1-30 µg/mL) without significant cytotoxicity demonstrated by its high adhesion inhibition ratio. The inhibition may result from its down-regulation on expression of integrin ß1 and α6, and CD44 on HT29 cells, as well as E-selectin on endothelial cells. Furthermore, G inhibited invasion and migration of HT29 cells. Pretreatment followed by one-month oral administration of G to the immunocompetent mice inoculated with mouse melanoma cells produced significant inhibition on lung metastasis without marked side effects. Collectively, this paradigm-shifting study provides, for the first time, a new strategy to discover safe and effective pre-metastatic chemopreventives from abortion TCM.

Bioactivity-guided fast screen and identification of cancer metastasis chemopreventive components from raw extracts of Murraya exotica.

Murraya exotica is a traditional Chinese medicine (TCM) widely grown in southeast China. We herein proposed a fast strategy for separation and identification of active components of cancer metastatic chemopreventives from the root, leaf, twig and stem bark extracts that were obtained by reflux in 80% acidic ethanol and then liquid-liquid extraction. High performance liquid chromatography (HPLC) analysis showed that the extract mixtures from leaf, bark and twig were similar, while the root extract contained a characteristic component (CM1). Bioactivity assays revealed that the root extract contained some active components that significantly inhibited cancer cell viability and migration. Ultra performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (UPLC-DAD-ESI-MS) analysis indicated the existence of coumarins in the root and leaf extracts. Semi-preparative chromatographic separation and physicochemical characterization indicated that CM1 was a novel coumarin derivative that warrants further chemopreventive studies on cancer metastasis. The present phytochemical and phytopharmacological studies exemplify a fast strategy for screening and identifying active component(s) from raw extracts of phytomedicines.