Curcumin enhances cisplatin sensitivity of human NSCLC cell lines through influencing Cu-Sp1-CTR1 regulatory loop.

BACKGROUND: Curcumin is a naturally occurring polyphenol which has been demonstrated to possess diverse biological activities. We previously reported that curcumin is a biologically active copper chelator with antitumor activity. Copper transporter 1 (CTR1) on the plasma membrane of eukaryotic cells mediates both copper as well as anticancer drug cisplatin uptake. PURPOSE: This study aims to investigate whether curcumin enhances cisplatin sensitivity of human non-small cell lung cancer (NSCLC) through influencing Cu-Sp1-CTR1 regulatory loop. METHODS: The combination effect of curcumin and cisplatin on cell proliferation and apoptosis was determined in vitro and in vivo. Platinum level in A549 cells and tumor tissue was measured by atomic absorption spectrometry (AAS). The binding ability of specificity protein 1 (Sp1) to CTR1 and Sp1 promoters was detected by ChIP assay and luciferase reporter assay system. RESULTS: Here we show that combined curcumin and cisplatin treatment markedly inhibited A549 cells proliferation and induced its apoptosis. Using a mouse model of A549 xenograft, we demonstrated that curcumin inhibits copper influx and increases uptake of platinum ion in tumor. Curcumin treatment enhances the binding of Sp1 to CTR1 and Sp1 promoters, thus induces CTR1 expression and chemosensitization to cisplatin treatment. This process is regulated by the Cu-Sp1-CTR1 regulatory loop. Moreover, the enhancement mediated by curcumin on cisplatin therapeutic efficacy in cultured human NSCLC cell lines (A549, H460, H1299) was dependent on CTR1. CONCLUSIONS: Our results demonstrated copper chelator curcumin enhances the benefits of platinum-containing chemotherapeutic agents and CTR1 could be a promising therapeutic target for non-small cell lung cancer treatment.

Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice.

The roots of Scutellaria baicalensis has been used as a remedy for inflammatory and infective diseases for thousands of years. We evaluated the antiviral activity against respiratory syncytial virus (RSV) infection, the leading cause of childhood infection and hospitalization. By fractionation and chromatographic analysis, we determined that baicalin was responsible for the antiviral activity of S. baicalensis against RSV infection. The concentration for 50% inhibition (IC50) of RSV infection was determined at 19.9 ± 1.8 µM, while the 50% cytotoxic concentration (CC50) was measured at 370 ± 10 µM. We then used a mouse model of RSV infection to further demonstrate baicalin antiviral effect. RSV infection caused significant lung injury and proinflammatory response, including CD4 and CD8 T lymphocyte infiltration. Baicalin treatment resulted in reduction of T lymphocyte infiltration and gene expression of proinflammatory factors, while the treatment moderately reduced RSV titers recovered from the lung tissues. T lymphocyte infiltration and cytotoxic T lymphocyte modulated tissue damage has been identified critical factors of RSV disease. The study therefore demonstrates that baicalin subjugates RSV disease through antiviral and anti-inflammatory effect.

Curcumin is a biologically active copper chelator with antitumor activity.

BACKGROUND: Curcumin is a natural product with antitumor activity. The compound targets multiple cell signaling pathways, including cell survival and proliferation, caspase activation and oncogene expression. As a ß-diketone, curcumin also exists as a keto-enol tautomer that chelates transition metal ions with high affinity. PURPOSE: Copper has an integral role in promoting tumor growth and angiogenesis. This study aims to investigate whether curcumin exerts its antitumor activity through copper chelation. METHODS: Copper chelation ability of curcumin was validated by measuring US/VIS spectrum. The antitumor activity and in vivo copper removal ability of curcumin was determined in a murine xenograft model. The effect of curcumin on copper-induced MAPK activation and cell proliferation was determined in cell culture system. RESULTS: Administration of curcumin to tumor-bearing animals resulted in suppression of A549 xenograft growth, an effect that was also observed in animals treated with ammonium tetrathiomolybdate (TM), a metal chelator used for copper storage disorders clinically. The inhibition on tumor growth was associated with reduction of copper concentrations in the serum of treated groups. In cell culture studies, we showed that copper promoted cell proliferation through Erk/MAPK activation. Treatment with curcumin or U0126, a specific MAPK inhibitor, or suppression of cellular uptake of copper by siRNA knockdown of copper transporter protein 1 (CTR1) blocked copper-induced cell proliferation. CONCLUSIONS: This study therefore demonstrates curcumin antitumor effect to its copper chelation capability. These results also implicate copper chelation as a general mechanism for their action of some biologically active polyphenols like flavonoids.

Induction of murine macrophage M2 polarization by cigarette smoke extract via the JAK2/STAT3 pathway.

Cigarette smoking is a major pathogenic factor in lung cancer. Macrophages play an important role in host defense and adaptive immunity. These cells display diverse phenotypes for performing different functions. M2 type macrophages usually exhibit immunosuppressive and tumor-promoting characteristics. Although macrophage polarization toward the M2 phenotype has been observed in the lungs of cigarette smokers, the molecular basis of the process remains unclear. In this study, we evaluated the possible mechanisms for the polarization of mouse macrophages that are induced by cigarette smoking (CS) or cigarette smoke extract (CSE). The results showed that exposure to CSE suppressed the production of reactive oxygen species (ROS) and nitric oxide (NO) and down-regulated the phagocytic ability of Ana-1 cells. The CD163 expressions on the surface of macrophages from different sources were significantly increased in in vivo and in vitro studies. The M1 macrophage cytokines TNF-α, IL-12p40 and enzyme iNOS decreased in the culture supernatant, and their mRNA levels decreased depending on the time and concentration of CSE. In contrast, the M2 phenotype macrophage cytokines IL-10, IL-6, TGF-ß1 and TGF-ß2 were up-regulated. Moreover, phosphorylation of JAK2 and STAT3 was observed after the Ana-1 cells were treated with CSE. In addition, pretreating the Ana-1 cells with the STAT3 phosphorylation inhibitor WP1066 inhibited the CSE-induced CD163 expression, increased the mRNA level of IL-10 and significantly decreased the mRNA level of IL-12. In conclusion, we demonstrated that the M2 polarization of macrophages induced by CS could be mediated through JAK2/STAT3 pathway activation.