Diterpenoids from Tetraclinis articulata that Inhibit Various Human Leukocyte Functions

Ten new compounds, eight of them pimarane derivatives (1-8), together with a menthane dimer (9) and a totarane diterpenoid (10), were isolated from the leaves and wood of Tetraclinis articulata. The structures of 1-10 were established by using spectroscopic techniques, including 2D NMR spectra. Pimaranes 1-5 were found to possess an unusual cis interannular union of the B and C rings, which, from a biogenetic perspective, could be derived from the hydration of a carbocation at C-8. Compounds 4-6 and a mixture of 7 and 11 modulated different human leukocyte functions at a concentration of 10 microM, mainly the degranulation process measured as myeloperoxidase release and, to a lesser extent,…

Modulatory effect of bolinaquinone, a marine sesquiterpenoid, on acute and chronic inflammatory processes

The marine metabolite bolinaquinone is a novel inhibitor of secretory phospholipase A(2) (sPLA(2)), with a potency on the human synovial enzyme (group II) higher than that of manoalide. This activity on the sPLA(2) was confirmed in vivo in the 8-h zymosan rat air pouch on the secretory enzyme accumulation in the pouch exudate. Additionally, bolinaquinone decreased potently the synthesis and release of leukotriene B(4) (LTB(4)) in calcimycin (A23187)-stimulated human neutrophils as a consequence of the inhibition of 5-lipoxygenase activity, as well as PGE(2) and NO production on zymosan-stimulated mouse peritoneal macrophages. This compound exerted anti-inflammatory effects by topical and or…

Tumor expression levels of CSC markers in resectable non-small cell lung cancer.

7562 Background: Cancer stem cells (CSCs) have been proposed as the driving force of tumorigenesis and the seeds of metastases. However, their existence and role remain a topic of intense debate. T...

Lung tumorspheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer

AbstractThe high resistance against current therapies found in non-small-cell lung cancer (NSCLC) has been associated to cancer stem-like cells (CSCs), a population for which the identification of targets and biomarkers is still under development. In this study, primary cultures from early-stage NSCLC patients were established, using sphere-forming assays for CSC enrichment and adherent conditions for the control counterparts. Patient-derived tumorspheres showed self-renewal and unlimited exponential growth potentials, resistance against chemotherapeutic agents, invasion and differentiation capacities in vitro, and superior tumorigenic potential in vivo. Using quantitative PCR, gene express…

62P Novel therapeutic strategies in NSCLC: Lung-tumorspheres as an effective in vitro screening platform

An expression signature characterizes cancer stem cells from lung adenocarcinoma patients

Synthesis, structural aspects and bioactivity of the marine cyclopeptide hymenamide C

Abstract Head-to-tail proline containing cyclopeptide hymenamide C [cyclo(Leu-Trp-Pro 3 -Phe-Gly-Pro 6 -Glu); 1 ], isolated from a marine sponge and for which a preliminary immunomodulating activity was reported, was efficiently synthesized by a three-dimensional orthogonal solid-phase strategy (Fmoc/tBu/Allyl) via anchoring the ω -carboxyl function of the glutamic acid to the solid support (PAC–PEG–PS). The linear precursor was entirely assembled and subsequently cyclized on resin, yielding a major product identical to the natural hymenamide C and a minor one, a geometric isomer of hymenamide C ( 2 ), differing for the geometry of peptide linkages at Pro residues. Both the ‘proline-rich’ c…

Abstract 3354: Characterization of lung tumorspheres by gene expression and flow cytometry: differential expression in CSC-related markers and signaling pathways

Abstract Chemoresistance, progression and metastasis have made of lung cancer the first cause of cancer mortality. These features were linked to a subpopulation of cells, named cancer stem cells (CSCs), which remain largely unknown. The aim of this study was to isolate and characterize CSCs from lung cancer cell-lines and tumor-tissue from resectable non-small cell lung cancer (NSCLC). Methods: Tumor cells from resected NSCLC and cell lines (H1650, H1993, A549, and PC9) were grown in monolayer and as spheroids. RTqPCR was performed to analyze the mRNA expression of CSCs-related genes: CSC-markers (EPCAM1, ALDH1A1, CD166, ABCG2, CD44, CD133); pluripotency genes (KLF4, OCT4, NANOG, SOX2, MYC,…

Synthesis and biological properties of the seven alanine-modified analogues of the marine cyclopeptide hymenamide C

The synthesis and biological activity of the marine cyclopeptide hymenamide C(1), showing an inhibitory effect on human neutrophil elastase degranulation release, were recently described. Based on this result, it was decided to undertake a systematic structure-activity relationship study of this cyclopeptide, based on the Ala-scan technique, in order to obtain useful information for the rational design of additional analogues. The synthesis and characterization of the seven Ala modified analogues are reported and their biological and pharmacological properties are described.

Cycloamphilectenes, a new type of potent marine diterpenes: inhibition of nitric oxide production in murine macrophages.

The inhibitory effect of a series of 6 cycloamphilectenes, novel marine diterpenes based on amphilectene skeletons and isolated from the Vanuatu sponge Axinella sp., on NO, PGE(2) and TNFalpha production in murine peritoneal macrophages was studied. These compounds reduced potently nitric oxide production in a concentration-dependent manner with IC(50) values in the submicromolar range (0.1-4.3 microM). Studies on intact cells and Western blot analysis showed that the more potent cycloamphilectenes reduced the expression of inducible nitric oxide synthase without affecting cyclo-oxygenase-2 expression. Among them cycloamphilectene 2, the unique compound bearing an exocyclic methylene group,…

Lung tumorspheres as a platform for testing new therapeutic strategies in lung cancer.

e23177Background: Resistance to treatment is one of the causes influencing the high mortality of lung cancer. This feature seems to be dependent of a small subset of special characteristics of self...

LAAE-14, a new anti-inflammatory drug, increases the survival ofCandida albicans-inoculated mice

LAAE-14, a lipidic acid-amido ether derivative, has been recently described as a new anti-inflammatory drug. We have studied the effect of treatment with this compound on the susceptibility of mice to in vivo experimental Candida albicans infection. ICR mice orally treated with LAAE-14 (25 mg kg(-1)) and experimentally intravenously infected showed a significantly increased survival as compared to control mice. In vitro, the compound did not inhibit the growth of C. albicans yeast cells or the yeast-to-hyphal transition. The in vitro production of prostaglandin E2 by peritoneal macrophages in response to the yeasts and hyphae of C. albicans was significantly decreased upon treatment with LA…

Prognostic Impact of Immune Microenvironment Markers in Tumor and Stroma in Resectable Nsclc

ABSTRACT Aim: Tumor-infiltrating immune cells have been proved to play an important role in tumor progression. In this study we have analyzed the expression of 11 immune related genes in both tumor and stroma samples of resectable NSCLC patients. Methods: In this retrospective study FFPE samples from 117 early-stage NSCLC patients of primary tumor tissue were used. The most representative areas of tumor and tumor stroma of each sample were carefully micro-dissected. RT-PCR using hydrolysis probes (TaqMan, Applied Biosystems) was performed to assess the expression of Treg markers such as: CD127, CD25, FOXP3, CTLA-4, IL-10, TGFB-1, LAG-3, GITR and TNFA as well as CD4 and CD8. Relative gene ex…

Abstract 1918: Gene characterization of lung-tumorspheres for their usage as an in vitro screening platform for testing new therapeutic strategies

Abstract Background: Lung cancer features like treatment resistance or tumor relapse have been linked to cancer stem cells (CSCs), a population of cells with self-renewal properties, and the ability to grow forming tumorspheres in non-adherent conditions. The aim of this study was to isolate and characterize tumorspheres from lung cancer cell lines and tumor tissue from resectable non-small cell lung cancer (NSCLC) patients and to use them as an in vitro platform for drug screening. Methods: This study was performed on cells from seven NSCLC tumor samples and five cell lines (H1650, H1993, H1395, A549 and PC9) grown in monolayer and as spheroids. The expression of 60 genes, including CSC-ma…

LAAE-14, a new in vitro inhibitor of intracellular calcium mobilization, modulates acute and chronic inflammation.

Abstract A new lipidic acid-amido ether derivative (LAAE-14) able to reduce dose-dependently the calcium increases mediated either by calcium ionophore ionomycin, by the endoplasmic reticular Ca 2+ -ATPase inhibitor thapsigargin, or by the chemotactic tripeptide N -formyl- l -methionyl- l -leucyl- l -phenylalanine (fMLP), in human neutrophils as well as in murine peritoneal macrophages, but not ATP, has been evaluated as a potential anti-inflammatory drug. This compound attenuated leukocyte activation by means of its inhibitory effect on the respiratory burst elicited in both types of cells by 12- O -tetradecanoyl phorbol 13-acetate, by inhibition of the degranulation process induced by cyt…

MA04.03 Lung Tumorspheres Characterization Reveals Cancer Stem-Like Cells Potential Targets and Prognostic Markers in Non-Small Cell Lung Cancer

Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer

Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by H-1-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC). We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids…

Characterization of lung tumourspheres reveals cancer stem-like cells potential targets and prognostic markers in non-small cell lung cancer

Abstract Background Non-small cell lung cancer (NSCLC) is the first cause of death cancer-related worldwide mainly due to high therapeutic resistance. This resistance is related to cancer stem-like cells (CSCs), for which the identification of targets and markers is still ongoing. Methods Primary cultures from 8 NSCLC patients were established as tumorspheres and as monolayers. CSCs properties were tested for both conditions in vitro and in vivo. The expression of 50 CSCs-related genes was assessed by RTqPCR and proteins of significantly overexpressed genes were examined by immunoblot and immunofluorescence. The prognostic role of these genes was analyzed in a cohort of 661 NSCLC patients f…

Future Trends, Challenges, and Opportunities with Polymer‐Based Combination Therapy in Cancer

Isolation and characterization of lung cancer sphere-forming cells as platforms for the development of new therapeutic strategies

e22190 Background: Resistance to treatment is one of major causes influencing the high mortality of lung cancer. This feature seems to be dependent of a minority of cancer cells with special charac...