Ji Won Park

Silver nanoparticles modify VEGF signaling pathway and mucus hypersecretion in allergic airway inflammation

The anti-inflammatory action of silver nanoparticles (NPs) has been reported in a murine model of asthma in a previous study. But more specific mechanisms of silver NPs in an attenuation of allergic airway inflammation have not yet been established. Vascular and mucous changes are believed to contribute largely in pathophysiology in asthma. Among various factors related to vascular changes, vascular endothelial growth factor (VEGF) plays a pivotal role in vascular changes in asthma. Mucin proteins MUC5AC and MUC5B have been implicated as markers of goblet cell metaplasia in lung pathologies. The aim of this study was to investigate the effects of silver NPs on VEGF signaling pathways and mucus hypersecretion. Ovalbumin (OVA)-inhaled female BALBc mice were used to evaluate the role of silver NPs and the related molecular mechanisms in allergic airway disease. In this study, with an OVA-induced murine model of allergic airway disease, it was found that the increased levels of hypoxia-inducible factor (HIF)-1α, VEGF, phosphatidylinositol-3 kinase (PI3K) and phosphorylated-Akt levels, and mucous glycoprotein expression (Muc5ac) in lung tissues were substantially decreased by the administration of silver NPs. In summary, silver NPs substantially suppressed mucus hypersecretion and PI3K/HIF-1α/VEGF signaling pathway in an allergic airway inflammation.

Attenuation of allergic airway inflammation and hyperresponsiveness in a murine model of asthma by silver nanoparticles

The use of silver in the past demonstrated the certain antimicrobial activity, though this has been replaced by other treatments. However, nanotechnology has provided a way of producing pure silver nanoparticles, and it shows cytoprotective activities and possible pro-healing properties. But, the mechanism of silver nanoparticles remains unknown. This study was aimed to investigate the effects of silver nanoparticles on bronchial inflammation and hyperresponsiveness. We used ovalbumin (OVA)-inhaled female C57BL/6 mice to evaluate the roles of silver nanoparticles and the related molecular mechanisms in allergic airway disease. In this study with an OVA-induced murine model of allergic airway disease, we found that the increased inflammatory cells, airway hyperresponsiveness, increased levels of IL-4, IL-5, and IL-13, and the increased NF-κB levels in lungs after OVA inhalation were significantly reduced by the administration of silver nanoparticles. In addition, we have also found that the increased intracellular reactive oxygen species (ROS) levels in bronchoalveolar lavage fluid after OVA inhalation were decreased by the administration of silver nanoparticles. These results indicate that silver nanoparticles may attenuate antigen-induced airway inflammation and hyperresponsiveness. And antioxidant effect of silver nanoparticles could be one of the molecular bases in the murine model of asthma. These findings may provide a potential molecular mechanism of silver nanoparticles in preventing or treating asthma.

Abstract A18: Silver nanoparticles induce apoptosis by regulation of cyclic AMP response element-binding protein in lung cancer cells

Recently, much effort has been devoted to the development of biomedical applications for nanoparticles (NPs). Silver NPs have been shown various therapeutic effects such as antimicrobial, antioxidant, and anti-inflammatory effects. Recently silver NPs have been shown to induce the apoptotic pathway in vitro. But exact mechanism is not yet established. We conducted this study to determine the mechanisms of silver NPs on cellular apoptosis in non-small cell lung cancer (NSCLC) cell lines using cyclic AMP response element-binding protein (CREB) activity which has been implicated to contribute an important pathobiologic role in lung carcinogenesis and is considered a potential therapeutic target for NSCLC. We hypothesized that constitutively increased CREB and its related signaling pathways can be blocked by silver NPs. To determine cytotoxic effect of silver NPs, several NSCLC cell lines were treated with various concentrations for different times. Among these lung cancer cell lines, H520, human lung squamous carcinoma cell lines, was the most sensitive. FACS analysis also showed that silver NPs induced cell death of H520 cells. Treating H520 cells with silver NPs (100, 200, or 500 M) inhibited CREB activation by blocking the activity of extracellular signal kinase/ribosomal s6 kinase and also by blocking the activity of phosphatidylinositol 3-kinase/Akt. We subsequently confirmed the expression of Bax and Bcl-2 in H520 cells was substantially regulated by silver NPs. We also demonstrated that silver NPs induced the cleavage of apoptosis-related proteins, poly (ADP-ribose) polymerase and caspase-3. In this study, we suggest that silver NPs induce apoptosis in H520 cells by regulation of CREB signaling pathways and may be useful as a therapeutic strategy for cancer. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A18.

Pemetrexed in Previously Treated Non-small Cell Lung Cancer Patients with Poor Performance Status

BACKGROUND AND OBJECTIVE Pemetrexed have been approved for the treatment of patients affected by advanced non-small cell lung cancer (NSCLC) in progression after first-line chemotherapy. We evaluated the activity and feasibility of pemetrexed in previously treated NSCLC. METHODS Patients with histologically or cytologically confirmed NSCLC were evaluated from April 2007 to March 2009. The patients had relapsed or progressed after prior chemotherapy treatment. Pemetrexed (500 mg/m²) was administered intravenously once every 3 weeks after progression to prior chemotherapy. The tumor response was evaluated according to RECIST criteria by chest CT at every 2 cycles of chemotherapy. RESULTS A total 61 patients were eligible for analysis. Performance status of them (100%) was over 2. The response rate and disease control rate were 14.7% and 37.7% respectively. Non-squamous cell carcinoma histology was significantly associated with a superior response rate (P=0.045) and disease control rate (P=0.008). The median survival time and the median progression free survival (PFS) time were 6.11 months and 2.17 months, respectively. Comparing the efficacy of pemetrexed in these two settings [second-line versus (12/61) more than third (49/61)], there was no significant difference in regard to median survival (11.18 months vs 11.46 months, P=0.922,5), but PFS was more longer in third- or further-line groups than second-line group (1.39 months vs 2.25 months, P=0.015,3). CONCLUSIONS Pemetrexed is a feasible regimen in previously treated NSCLC with poor performance status.