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Background: Clerodendrum inerme is a folk medicinal plant used in the treatment of various illnesses such as a cough, scrofulous infection, venereal infection, skin diseases and tumors. It exhibited many pharmacological effects including hepatoprotective, anti-inflammatory, anti- bacterial, anti-oxidant and anticancer properties. Objective: The purpose of this study was to investigate the influence of methanolic extract of C. inerme leaves on migration, invasion and adhesion activities on human lung adenocarcinoma. Materials and methods: Cytotoxicity, cell motility, migration, invasion and adhesion abilities were detected by MTT, wound healing, trans-well mobilization, modified Boyden chamber and cell adhesion assay, respectively. Results: The results demonstrated that up to 400 µg/mL methanolic leaves extract has low toxicity on A549 cells showing more than 50% cell viability. At non-cytotoxic and sub-toxic doses (200 and 400 µg/mL) of methanolic leave extract significantly suppressed cell motility, migration, invasion and cell adhesion compared with the untreated control. Conclusion: These results suggested that methanolic leaves extract of C. inerme inhibited migration, invasion and adhesion of A549 cells. These findings showed new therapeutic potential for C. inerme in anti-metastatic therapy. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that inflammatory microenvironment facilitates tumor metastasis. Here, we found that LFG-500, a novel synthetic flavonoid, significantly inhibited epithelial–mesenchymal transition (EMT) in human lung adenocarcinoma A549 and H1299 cells co-cultured with LPS-challenged THP-1 cells or cultured in THP-1 cell-derived conditioned medium. Moreover, we found that TNF-α is a direct and decisive factor for promoting EMT and LFG-500 suppressed TNF-α-induced EMT and cell motility. NLRP3 knockdown inactivated NLRP3 inflammasome, which subsequently inhibited EMT and blocked cell migration, indicating that TNF-α-induced EMT requires the NLRP3 inflammasome. LFG-500 inhibited the activation of the NLRP3 inflammasome, thus inhibiting EMT. Moreover, LFG-500 treatment significantly inhibited metastasis in vivo by downregulating NLRP3 expression. Importantly, we found that NLRP3 was highly expressed in high-grade lung adenocarcinoma and that its expression was correlated with lymph node metastasis. NLRP3 and vimentin levels were significantly increased in matched metastatic lymph nodes. Moreover, a significant positive correlation was observed between their levels. Together, these results suggest that LFG-500 markedly suppresses EMT by inhibiting the NLRP3 inflammasome in the inflammatory microenvironment and that NLRP3 is a potential biomarker of lung adenocarcinoma metastasis. [ABSTRACT FROM AUTHOR]

Despite the increasing lung cancer-associated death rate, its therapy has been constrained by impasse of early diagnosis. To apply non-invasive imaging for potential cancer diagnosis system, we screened human lung adenocarcinoma-specific peptides using the phage display technique. For in vivo phage-displayed peptide screening, M13 phage library displaying 2.9 × 10 random peptides was injected through tail vein to lung adenocarcinoma cell-derived xenograft mouse model. Through four rounds of biopanning, a specific peptide sequence (CAKATCPAC) was screened out with the highest frequency and was named as Pep-1, and it was analyzed for its targeting ability as an imaging probe by in vitro competitive assay to test its cell-binding ability, immunohistochemical detection in the tumor tissue, and in vivo NIR fluorescent optical imaging. The specificity of Pep-1 toward lung cancer was ensured by in vivo imaging using xenograft animals of various cancer types. The results suggest that Pep-1 is a promising diagnostic lead molecule for rapid and accurate detection of human lung adenocarcinoma. In addition, it was found that the targeting ability was much enhanced by ionizing radiation in both cell-derived and patient-derived lung adenocarcinoma xenografts, suggesting the possibility of applying Pep-1 for prognostic diagnosis after radiotherapy. Taken together, this study suggests that Pep-1 possesses a specific-targeting ability for human lung adenocarcinoma and that this peptide could be directly used as a clinically applicable imaging probe. [ABSTRACT FROM AUTHOR]

Melatonin is an indoleamine synthesized in the pineal gland that shows a wide range of physiological and pharmacological functions, including anticancer effects. In this study, we investigated the effect of melatonin on drug-induced cellular apoptosis against the cultured human lung adenocarcinoma cells and explored the role of histone deacetylase ( HDAC) signaling in this process. The results showed that melatonin treatment led to a dose- and time-dependent decrease in the viability of human A549 and PC9 lung adenocarcinoma cells. Additionally, melatonin exhibited potent anticancer activity in vitro, as evidenced by reductions of the cell adhesion, migration, and the intracellular glutathione ( GSH) level and increases in the apoptotic index, caspase 3 activity, and reactive oxygen species ( ROS) in A549 and PC9 cells. Melatonin treatment also influenced the expression of HDAC-related molecules ( HDAC1 and Ac-histone H3), upregulated the apoptosis-related molecules ( PUMA and Bax), and downregulated the proliferation-related molecule ( PCNA) and the anti-apoptosis-related molecule (Bcl2). Furthermore, the inhibition of HDAC signaling using HDAC1 si RNA or SAHA (a potent pan-inhibitor of HDACs) sensitized A549 and PC9 cells to the melatonin treatment. In summary, these data indicate that in vitro-administered melatonin is a potential suppressor of lung adenocarcinoma cells by the targeting of HDAC signaling and suggest that melatonin in combination with HDAC inhibitors may be a novel therapeutic intervention for human lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Dietary polyphenols have been reported as an effective phytochemical for health protection and cinnamic acid (CA) is one of the polyphenols that has been demonstrated having chemopreventive potential. It was known that the early and distal metastasis might lead to the high mortality of patients with lung adenocarcinoma. We previously compared and verified the inhibitory effect of cis-CA and trans-CA on phorbol-12-myristate-13-acetate (PMA)-induced invasion of human lung adenocarcinoma A549 cells. The aim of this study was to explore the underlying molecular mechanism. By gelatin zymography and semi-quantitative RT-PCR, the activities and mRNA of MMP-9/MMP-2 exerted a significantly (p <.05) dose-dependent reduction by treating with cis-CA and trans-CA. Western blots further showed that the cis-CA- and trans-CA-inhibited MMPs might partly through modulating TIMP-1 and the PAI-2-regulated uPA activity. In molecular level, the AP-1 and NF-κB as well as the downstream of the MAPK pathway might be involved in cis-CA- and trans-CA-inhibited MMPs expression. This study disclosed the molecular mechanism underlying the anti-invasive activity of cis-CA and trans-CA and concluded the cis- and trans-form of CA should be a safe and potential agent to prevent lung tumor cells from metastasizing. [Copyright &y& Elsevier]

Survivin is a member of the inhibitors of apoptosis protein (IAP) family and is highly expressed in various cancer cells. However, the molecular mechanisms regulating survivin expression remain unclear. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) in regulating survivin in the human lung adenocarcinoma cell line H1355 in response to arsenic trioxide (As(3+)). Our data indicated that As(3+) induced cytotoxicity accompanied by down-regulation of survivin, cleavage of Poly ADP-ribosyl polymerase (PARP) and activations of MAPKs, including ERK1/2, p38 and c-jun N-terminal kinase (JNK). We found that blockage of p38 or JNK activation attenuated the As(3+)-induced survivin down-regulation and PARP cleavage with significant reversal of cell viability, however, by only 5–8%. On the other hand, the MEK inhibitor PD098059 or the ubiquitin-proteasome inhibitor MG-132 exhibited little effect on survivin down-regulation and PARP cleavage induced by As(3+). In this study, we demonstrated that As(3+) could down-regulate survivin via activations of p38 and JNK in an ubiquitin-proteasome independent pathway and lead to cytotoxicity and apoptosis in the human lung adenocarcinoma cell line H1355. [ABSTRACT FROM AUTHOR]

We recently reported the isolation of a novel actin-related gene, Arp11, from a PC-14 human lung adenocarcinoma clone with low metastatic and tumorigenic ability. In this paper, we report the effect of Arp11 expression on PC-14 tumor growth. We transfected a highly metastatic and tumorigenic PC-14 line, Lu-2, with an Arp11 expression vector, and obtained five stable transfectants that each express Arp11 at different levels. The tumor growth rate of these transformants in nude mice and their colony formation in soft agar were reduced in proportion to their levels of Arp11 expression. Thus, overexpression of Arp11 may suppress tumorigenicity in nude mice. The morphology of the transfectants expressing high levels of Arp11 differed clearly from that of Lu-2 and the mock-transfectants as the Arp11-transfectants were flat and fibrous, while Lu-2 and the mock-transfectants were round and were released into the culture medium. An increase in the number of actin stress fibers was observed in the Arp11-transfectants 1-12-3-x and 2-9-2 but not in the mock-transfected lines. Our results suggest that the overexpression of Arp11 regulates the transcription of multiple genes that are involved in suppressing tumorigenicity. [Copyright &y& Elsevier]

Using the intrabronchial orthotopic propagation method, we evaluated the biological characteristics of human adenocarcinoma cell lines in vivo and examined the expressions of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and their related proteins. Nine human lung adenocarcinoma cell lines, including A549, NCI-H23, NCI-H322, NCI-H358, Calu-3, PC-14, LC-2/ad, RERF-LC-KJ and PL16T, were injected into the peripheral bronchi of mice using this method. The mice were sacrificed at 4 and 8 weeks after tumor cell propagation and the lungs and other organs were observed macroscopically and histologically. We classified the adenocarcinoma cell lines, according to their intrapulmonary tumorigenicity, into the following three groups: (A) those that showed a high incidence of intrapulmonary implantation (>50%) (A549 and NCI-H358). A549 showed mediastinal lymph node metastasis and pleural dissemination; (B) those that showed a low incidence of intrapulmonary implantation (PC-14, NCI-H322, NCI-H23, Calu-3, and LC-2/ad); (C) those that showed no tumorigenicity in the lung (RERF-LC-KJ and PL16T). In order to characterize the biological differences between each cell line, we investigated the expressions of MMP-2 and MMP-9 and their related molecules by northern blot analysis. The expressions of MMP-2 and MMP-9 and their activators (membrane-type 1-MMP and urokinase-type plasminogen activator) were thought to be associated with the growth, invasion and metastasis of the human lung adenocarcinoma cell lines examined. [Copyright &y& Elsevier]

Metastatic human lung adenocarcinoma HAL-8Luc cells display an enhanced expression of α(1,3)-fucosyltransferases (α(1,3)-Fuc-Ts) compared with their non-metastatic counterpart HAL-24Luc cells. This correlates with an increased surface expression of Lewisx(Lex)- and Lewisa(Lea)-related molecules and an in vitro enhanced adhesive capacity to E-selectin-expressing endothelial cells (Martin-Satué et al (1998). Cancer Res: 1544–1550). In the present work we have stably transfected HAL-24Luc cells with the cDNAs for the α(1,3)-Fuc-TIV and VII enzymes and analysed by flow cytometry the expression of Lex, sialyl-Lex, sialyl-Lexdimeric, Leaand sialyl-Lea. Fuc-TVII transfectants exclusively overexpress sialyl-Lexwhile Fuc-TIV-transfected cells only overexpress the Lexoligosaccharide. We show that solely Fuc-TVII transfectants are able to adhere to interleukin-1β-stimulated HUVEC monolayers. We also demonstrate that Fuc-TVII overexpression in HAL-24Luc cells is sufficient for the acquisition of the lung colonization phenotype. This is the first report directly showing the contribution of an α(1,3)-Fuc-T to the metastatic behaviour of human lung adenocarcinoma cells. [ABSTRACT FROM AUTHOR]