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Schmitt C.,Upper Alsace University | Voegelin M.,University of Strasbourg | Marin A.,Upper Alsace University | Schmitt M.,Upper Alsace University | And 4 more authors.
Bioorganic and Medicinal Chemistry

Aminopeptidase-N (APN/CD13) is highly expressed on the surface of numerous types of cancer cells and particularly on the endothelial cells of neoangiogenic vessels during tumourigenesis. This metallo-aminopeptidase has been identified as a potential target for cancer chemotherapy. In this work, we evaluated the efficacy of a novel series of benzosuberone analogues, which were previously reported to be highly potent, selective APN inhibitors with Ki values in the micromolar to sub-nanomolar range. Endothelial cell morphogenesis as well as cell motility were inhibited in vitro in a dose-dependent manner at concentrations that correlated with the potency of the compounds, thus confirming the key role of APN in these established models of angiogenesis. We report toxicity studies in mice showing that these compounds are well tolerated. We report the effects of the compounds, used alone or in combination with rapamycin, on the growth of a select panel of tumours that were subcutaneously xenografted onto Swiss nude mice. Our data indicate that the in vivo efficacy of these new APN inhibitors during the initial phase of tumour growth can be ascribed to their anti-angiogenic activities. However, we also provide evidence that these compounds are effective against established solid tumours. For colonic tumours, the anti-tumour effect depends on the level of APN expression in epithelial cells, and APN expression is associated with down-regulation of the transcription factor HIF-1α. These effects seem to be distinct from those of rapamycin. Our finding that the anti-tumour effect of the inhibitors in the colon requires APN expression strongly suggests that APN plays a crucial function in tumour cells that is distinct from its known role in neovascularisation. © 2013 Elsevier Ltd. All rights reserved. Source

Sovalat H.,Institute Of Recherche En Hematologie Et Transplantation | Scrofani M.,Institute Of Recherche En Hematologie Et Transplantation | Eidenschenk A.,Institute Of Recherche En Hematologie Et Transplantation | Pasquet S.,Institute Of Recherche En Hematologie Et Transplantation | And 2 more authors.
Experimental Hematology

Objective: Recently, we demonstrated that normal human bone marrow (hBM)-derived CD34 + cells, released into the peripheral blood after granulocyte colony-stimulating factor mobilization, contain cell subpopulations committed along endothelial and cardiac differentiation pathways. These subpopulations could play a key role in the regeneration of post-ischemic myocardial lesion after their direct intracardiac delivery. We hypothesized that these relevant cells might be issued from very small embryonic-like stem cells deposited in the BM during ontogenesis and reside lifelong in the adult BM, and that they could be mobilized into peripheral blood by granulocyte colony-stimulating factor. Materials and Methods: Samples of normal hBM and leukapheresis products harvested from cancer patients after granulocyte colony-stimulating factor mobilization were analyzed and sorted by multiparameter flow cytometry strategy. Immunofluorescence and reverse transcription quantitative polymerase chain reaction assays were performed to analyze the expression of typical pluripotent stem cells markers. Results: A population of CD34 +/CD133 +/CXCR4 +/Lin - CD45 - immature cells was first isolated from the hBM or from leukapheresis products. Among this population, very small (2-5 μm) cells expressing Oct-4, Nanog, and stage-specific embryonic antigen-4 at protein and messenger RNA levels were identified. Conclusions: Our study supports the hypothesis that very small embryonic-like stem cells constitute a " mobile" pool of primitive/pluripotent stem cells that could be released from the BM into the peripheral blood under the influence of various physiological or pathological stimuli. In order to fully support that hBM- and leukapheresis product-derived very small embryonic-like stem cells are actually pluripotent, we are currently testing their ability to differentiate in vitro into cells from all three germ layers. © 2011 ISEH - Society for Hematology and Stem Cells. Source

Sovalat H.,Institute Of Recherche En Hematologie Et Transplantation | Scrofani M.,Institute Of Recherche En Hematologie Et Transplantation | Eidenschenk A.,Institute Of Recherche En Hematologie Et Transplantation | Henon P.,Institute Of Recherche En Hematologie Et Transplantation
Stem Cells International

The purpose of our study was to determine whether the number of human very small embryonic-like stem cells (huVSELs) would vary depending on the age of humans. HuVSELs frequency was evaluated into the steady-state (SS) peripheral blood (PB) of healthy volunteers using flow cytometry analysis. Their numbers were compared with volunteers' age. Blood samples were withdrawn from 28 volunteers (age ranging from 20 to 70 years), who were distributed among three groups of age: "young" (mean age, 27.8 years), "middle" (mean age, 49 years), and "older" (mean age, 64.2 years). Comparing the three groups, we did not observe any statistically significant difference in huVSELs numbers between them. The difference in mRNA expression for PSC markers as SSEA-4, Oct-4, Nanog, and Sox2 between the three groups of age was not statistically significant. A similar frequency of huVSELs into the SS-PB of young, middle-aged, and aged subjects may indicate that the VSELs pool persists all along the life as a reserve for tissue repair in case of minor injury and that there is a continuous efflux of these cells from the BM into the PB. © 2016 Hanna Sovalat et al. Source

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