Garcimultiflorone K from Garcinia multiflora attenuates hepatocellular carcinoma metastasis by suppressing transforming growth factor-ß signaling.

BACKGROUND: Transforming growth factor­ß (TGF-ß) signaling is a crucial inducer of tissue fibrosis and extracellular matrix accumulation and a vital suppressor of epithelial cell proliferation and cancer metastasis. The nature of this multifunctional cytokine has prompted the development of TGF-ß signaling inhibitors as therapeutic agents. Our research group has recently isolated the polyprenylated polycyclic acylphloroglucinol garcimultiflorone K (GMK) from the stems of Garcinia multiflora; GMK exhibits antiangiogenic activity in endothelial cells. PURPOSE: In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Garcimultiflorone K in hepatocellular carcinoma cells. METHODS: Cell proliferation and viability were evaluated using the MTT assay. The migratory ability of HepG2 cells was measured using wound healing assays. The inhibitory effect of GMK against the nuclear translocation of Smad by TGF-ß was assessed through immunofluorescence staining and Western blotting. To investigate TGF-ß-dependent gene expression profiles upon GMK stimulation, RNA transcript levels were determined using reverse transcription polymerase chain reaction. The effects of GMK in Smad2-driven transcriptomic activities were studied using a reporter gene assay. Protein levels were detected using Western blotting. RESULTS: Our data revealed that GMK inhibited TGF-ß-induced cellular responses, including Smad protein phosphorylation, cell migration, and extracellular matrix production, during epithelial-mesenchymal transition (EMT). Mechanistic studies further demonstrated that GMK suppressed TGF-ß signaling by downregulating TGF-ß receptor II (TßRII). CONCLUSION: These findings elucidate that TßRII expression in hepatic cells can be specifically suppressed by GMK to attenuate metastasis and the disease-promoting effects of EMT, representing a therapeutic approach.

Tormentic acid inhibits H2O2-induced oxidative stress and inflammation in rat vascular smooth muscle cells via inhibition of the NF-κB signaling pathway.

Tormentic acid (TA) is a triterpene isolated from the stem bark of the plant Vochysia divergens and has been reported to exhibit anticancer, anti­inflammatory and anti­atherogenic properties. However, the functions of TA in hydrogen peroxide (H2O2)­induced oxidative stress and inflammation in rat vascular smooth muscle cells (RVSMCs) remain unclear. Therefore, the present study aimed to investigate whether TA suppressed H2O2­induced oxidative stress and inflammation in RVSMCs, and to determine its molecular mechanisms. The present study demonstrated that TA inhibited reactive oxygen species (ROS) generation, induced H2O2 in RVSMCs, and inhibited H2O2-induced expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase (NOX) in RVSMCs. In addition, TA significantly decreased the production of tumor necrosis factor­α (TNF­α), interleukin 6 (IL­6) and IL­1ß. Furthermore, TA pretreatment prevented nuclear factor­κB (NF­κB) subunit p65 phosphorylation and NF­κB inhibitor α (IκBα) degradation induced by H2O2 in RVSMCs. TA is, therefore, suggested to inhibit H2O2-induced oxidative stress and inflammation in RVSMCs via inhibition of the NF­κB signaling pathway. TA may have potential as a pharmacological agent in the prevention or treatment of atherosclerosis.

Antitumor effects of polysorbate-80 coated gemcitabine polybutylcyanoacrylate nanoparticles in vitro and its pharmacodynamics in vivo on C6 glioma cells of a brain tumor model.

Polybutylcyanoacrylate (PBCA) nanoparticles coated with polysorbate-80 have been extensively studied for delivery of drugs into the animal models; however, 1% polysorbate-80 coated gemcitabine PBCA nanoparticles (GCTB-PBCA-NPs) remain unknown. In this study, we investigated the inhibitory effects of brain targeted 1% polysorbate-80 coated GCTB-PBCA-NPs on C6 glioma cells in vitro and in vivo. GCTB-PBCA-NPs were prepared by emulsion polymerization and freeze drying. C6 glioma cells treated with 1% polysorbate-80 coated GCTB-PBCA-NPs showed poor growth with less cell density and increased detachment. Cell morphology was also greatly altered with nuclear vacuoles, ruptured cells and dead cells. Meanwhile, by flow cytometry, the numbers of cells treated with 1% polysorbate-80 coated GCTB-PBCA-NPs showed increase in G0/G1 phase and decreased in the S phase (P<0.01) compared with the blank control. CCK-8 assay also showed that GCTB could significantly inhibited cell proliferation in a concentration dependent manner. Finally, various preparations were injected (90 mg preparation per kg body weight) into the brain tumor model, which was produced after inoculating C6 glioma cells into Sprague Dawley (SD) rats for 14 days, it was shown that 1% polysorbate-80 coated GCTB-PBCA-NPs could significantly extend the survival time compared with the saline control (P<0.05). Taken together, 1% polysorbate-80 coated GCTB-PBCA-NPs can effectively inhibit the growth of C6 glioma cells in vitro and enhance antitumor activity on brain tumor in vivo.