The anti-infection drug furazolidone inhibits NF-κB signaling and induces cell apoptosis in small cell lung cancer.

Targeting nuclear factor kappa B (NF-κB) signaling pathway has become a promising strategy for the development of new antitumor drugs. In this paper, we found that anti-infection drug furazolidone (FZD) could significantly inhibit NF-κB-driven luciferase activity, and FZD could markedly inhibit both of the constitutive and tumor necrosis factor-α (TNFα)-triggered phosphorylation of NF-κB p65 in small cell lung cancer (SCLC). Further studies revealed that FZD inhibited the expression of inhibitor of kappa B kinase ß (IKKß) in SCLC cells. In addition, we found that FZD had significant antitumor activities in SCLC cells. FZD could markedly suppress the cell viability of SCLC cells dose-dependently, and FZD could significantly induce the cleavages of poly ADP-ribose polymerase (PARP) and Caspase3, the biomarkers of cell apoptosis, in SCLC cells. The flow cytometry also revealed that FZD induced cell apoptosis in SCLC cells. Finally, we also found that overexpression of constitutively activated IKKß could significantly abolish FZD-induced cell growth inhibition in SCLC cells, which further confirmed that FZD displayed its anti-SCLC activity through regulating NF-κB signaling pathway.

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small-cell lung cancer.

The proto-oncogene MDM2 is a nuclear-localized E3 ubiquitin ligase, which promotes tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. In this study, the anti-infective drug nitroxoline (NXQ) was screened out to effectively inhibit cell survival of small-cell lung cancer (SCLC) cells, and induce SCLC cell apoptosis by suppressing antiapoptotic proteins (such as Bcl-2 and MCL1) and upregulating proapoptotic protein Bim. In the mechanistic study, NXQ was found to downregulate MDM2 expression by inducing its proteasomal degradation, and thus upregulated p53 expression, which was a substrate protein of MDM2. Moreover, overexpression of MDM2 decreased the cytotoxicity of NXQ on SCLC cells. These results demonstrated that NXQ displayed anti-SCLC activity by suppressing MDM2 expression, which suggested that anti-infective NXQ had potential for SCLC treatment by targeting the MDM2/p53 axis.

MicroRNA-26b suppresses tumorigenicity and promotes apoptosis in small cell lung cancer cells by targeting myeloid cell leukemia 1 protein.

The aim of this study was to investigate the role of microRNA-26b (miR-26b) in regulating the proliferation, migration, and apoptosis of small cell lung cancer (SCLC) cells. First, we examined the expression level of miR-26b in human normal fetal lung fibroblasts (NFLFs) and three SCLC cell lines NCI-H466, NCI-H1688, and NCI-H196. In the following experiments, the three SCLC cell lines were transfected with miR-26b mimic and inhibitor. Cell growth and survival, as well as migration and invasion capacities were determined by MTT, colony formation, Transwell migration and invasion, and wound healing assays. Cell apoptosis, production of reactive oxygen species, and mitochondrial membrane potential were also measured in the three cell lines following various treatments. As a result, we found that the level of miR-26b was significantly lower in SCLC cells than in NFLFs. Additionally, transfection with miR-26b mimic could inhibit proliferation, colony formation, and migration, as well as induce apoptosis in these SCLC cell lines; while miR-26b inhibitor showed the opposite effects. Further mechanistic experiment revealed that miR-26b could suppress the expression of myeloid cell leukemia 1 protein (Mcl-1) and the 3'-untranslated region (3'-UTR) of Mcl-1 may be the direct binding site of miR-26b, suggesting that the effect of miR-26b may be mediated by targeting Mcl-1. Collectively, our findings offer a new insight into the role of miR-26b in the pathogenesis of SCLC, and provide primary evidence supporting the potential of miR-26b-based therapy for the treatment of SCLC.

Curcumin inhibits hepatocellular carcinoma growth by targeting VEGF expression.

Morbidity and mortality owing to hepatocellular carcinoma (HCC), the most common primary liver cancer, has increased in recent years. Curcumin is a polyphenol compound that has been demonstrated to exert effective antiangiogenic, anti-inflammatory, antioxidant, and antitumor effects. However, its clinical effects in HCC remain elusive. The main aim of the present study was to determine the antiangiogenic effects of curcumin in HCC. H22HCC cells were treated with different concentrations of curcumin in vitro. In addition, a mouse xenograft model was used and analyzed for expression levels of vascular endothelial growth factor (VEGF) protein and proteins of the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT) signaling pathway. Curcumin treatment inhibited H22 cell proliferation and promoted H22 cell apoptosis in a dose-dependent manner in vitro. In addition, curcumin treatment inhibited tumor growth in vivo at the concentrations of 50 and 100 mg/kg. Furthermore, curcumin treatment significantly decreased VEGF expression and PI3K/AKT signaling. The present findings demonstrated that curcumin inhibited HCC proliferation in vitro and in vivo by reducing VEGF expression.

Melatonin inhibits proliferation and invasion via repression of miRNA-155 in glioma cells.

Melatonin, an indolamine mostly synthesized in the pineal gland, exerts the anti-cancer effect by various mechanisms in glioma cells. Our previous study showed that miR-155 promoted glioma cell proliferation and invasion. However, the question of whether melatonin may inhibit glioma by regulating miRNAs has not yet been addressed. In this study, we found that melatonin (100µM, 1µM and 1nM) significantly inhibited the expression of miR-155 in human glioma cell lines U87, U373 and U251. Especially, the lowest expression of miR-155 was detected in 1µM melatonin-treated glioma cells. Melatonin (1µM) inhibits cell proliferation of U87 by promoting cell apoptosis. Nevertheless, melatonin had no effect on cell cycle distribution of U87 cells. Moreover, U87 cells treated with 1µM melatonin presented significantly lower migration and invasion ability when compared with control cells. Importantly, melatonin inhibited c-MYB expression, and c-MYB knockdown reduced miR-155 expression and migration and invasion in U87 cells. Taken together, for the first time, our findings show that melatonin inhibits miR-155 expression and thereby represses glioma cell proliferation, migration and invasion, and suggest that melatonin may downregulate the expression of miR-155 via repression of c-MYB. This will provide a theoretical basis for revealing the anti-glioma mechanisms of melatonin.

The tumor suppressor p53 regulates autophagosomal and lysosomal biogenesis in lung cancer cells by targeting transcription factor EB.

The cellular protein degradation system, such as proteasomal or autophagy-lysosomal system plays an important role in the pathogenesis of a variety of human diseases including cancer. Transcription factor EB (TFEB) is a master transcriptional factor in the regulation of autophagy-lysosome pathway (ALP), and it has multiple biological functions including protein degradation, cell homeostasis and cell survival. In the present study we show that the tumor suppressor p53 can regulate TFEB nuclear translocation and activity in lung cancer cells. We found p53 deletion or chemical inhibition of p53 using pifithrin-α could promote the translocation of TFEB from cytoplasm to the nucleus, thus increased the TFEB-mediated lysosomal and autophagosomal biogenesis in lung cancer cells. Moreover, re-expression of p53 could decrease the expression levels of TFEB-targeting genes involved in ALP, and knockdown of TFEB could abolish the effect of p53 on the regulation of ALP gene expression. Taken together, our data indicate that p53 affects ALP through regulating TFEB nuclear translocation in lung cancer cells. Importantly, our study reveals a critical link between two keys factors in tumourigenesis and autophagy, and suggests a potential important role of p53-TFEB signaling axis in lung cancer.

TaOx decorated perfluorocarbon nanodroplets as oxygen reservoirs to overcome tumor hypoxia and enhance cancer radiotherapy.

Cancer radiotherapy (RT) is a clinically used tumor treatment strategy applicable for a wide range of solid tumors. However, during RT treatment of tumors, only a small portion of applied ionizing irradiation energy is absorbed by the tumor, in which the largely hypoxic microenvironment also limits the anti-tumor efficacy of RT. In this work, we rationally fabricate polyethylene glycol (PEG) stabilized perfluorocarbon (PFC) nano-droplets decorated with TaOx nanoparticles (TaOx@PFC-PEG) as a multifunctional RT sensitizer. The obtained TaOx@PFC-PEG nanoparticles on one hand can absorb X-ray by TaOx to concentrate radiation energy within tumor cells, on the other hand after saturating PFC with oxygen will act as an oxygen reservoir to gradually release oxygen and improve tumor oxygenation. As the result, remarkably enhanced in vivo RT treatment is achieved with TaOx@PFC-PEG nanoparticles in our mouse tumor model experiments. Our work thus presents a new nanotechnology strategy to enhance RT-induced tumor treatment by simultaneously concentrating radiation energy within tumors and improving tumor oxygenation, using one multifunctional agent.

Serum pleiotrophin could be an early indicator for diagnosis and prognosis of non-small cell lung cancer.

AIMS: Pleiotrophin (PTN), an angiogenic factor, is associated with various types of cancer, including lung cancer. Our aim was to investigate the possibility of using serum PTN as an early indicator regarding disease diagnosis, classification and prognosis, for patients with non-small cell lung cancer (NSCLC). METHODS: Significant differences among PTN levels in patients with small cell lung cancer (SCLC, n=40), NSCLC (n=136), and control subjects with benign pulmonary lesions (n=21), as well as patients with different pathological subtypes of NSCLC were observed. RESULTS: A serum level of PTN of 300.1 ng/ml, was determined as the cutoff value differentiating lung cancer patients and controls, with a sensitivity and specificity of 78.4% and 66.7%, respectively. Negative correlations between serum PTN level and pathological differentiation level, stage, and survival time were observed in our cohort of patients with NSCLC. In addition, specific elevation of PTN levels in pulmonary tissue in and around NSCLC lesions in comparison to normal pulmonary tissue obtained from the same subjects was also observed (n=2). CONCLUSION: This study suggests that the serum PTN level of patients with NSCLC could be an early indicator for diagnosis and prognosis. This conclusion should be further assessed in randomized clinical trials.

[Expression and clinical significance of secretory leucocyte protease inhibitor in colon carcinoma].

OBJECTIVE: To investigate the expression of secretory leucocyte protease inhibitor (SLPI) in colon cancer and their clinical significance. METHODS: Immunohistochemistry was performed to detect the SLPI expression in colon cancer tissue microarray. The expression of SLPI was scored by two pathologists and was analyzed using Χ(2) test to explore its influence on the pathologic characteristics of colon carcinoma. RESULTS: SLPI was up-regulated in colon cancer tissue compared to normal mucosa. Overexpression of SLPI protein was correlated with differentiation grade (low differentiation: 42.1% vs 57.9%; moderate/well differentiation: 2.3% vs 97.7%, TNM stages(III-IV:29.4% vs 70.6%;I-II:3.1% vs 96.9%), lymph node metastasis (28.6% vs 71.4%) and distant metastasis (84.6% vs 15.4%), but not with patient age or sex. CONCLUSION: SLPI overexpression correlates with aggressive pathologic characteristics of colon cancer and it may server as prognostic factor of colon cancer patients. Further research will be carried out to verify whether SLPI can become a new target for colon cancer treatment.