Antiangiogenesis Is Produced by Nontoxic Doses of Vinblastine

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4143-4155 ◽  
Author(s):  
Angelo Vacca ◽  
Monica Iurlaro ◽  
Domenico Ribatti ◽  
Monica Minischetti ◽  
Beatrice Nico ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Wide Spectrum ◽  
Chorioallantoic Membrane ◽  
Ultrastructural Level ◽  
Matrix Metalloproteinase 2 ◽  
Cell Functions ◽  
Dose Dependent Fashion ◽  
Dose Dependent

The effects of vinblastine (VBL) on endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, spreading on fibronectin (FN), secretion of matrix-metalloproteinase-2 (MMP-2) and MMP-9, and morphogenesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. In vitro, at noncytotoxic doses (0.1, 0.25, 0.5, 0.75, and 1 pmol/L), VBL impacted all these functions, except secretion of MMPs, in a dose-dependent fashion. By contrast, proliferation of other primary cells such as fibroblasts and lymphoid tumor cells was not impacted. In vivo, VBL at 0.5, 0.75, and 1 pmol/L again displayed a dose-dependent antiangiogenic activity. Lack of cytotoxicity in vitro and in vivo was shown both morphologically, and also because the antiangiogenic effects were rapidly abolished when VBL was removed. Apoptosis was not induced. At the ultrastructural level, impairment of cell functions in vitro was associated with thin disturbance of the cytoskeleton, in the form of slight depolymerization and accumulation of microfilaments, which was equally reversible. Results suggest that VBL has an antiangiogenic component at very low, noncytotoxic doses, and that antiangiogenesis by VBL could be used to treat a wide spectrum of angiogenesis-dependent diseases, including certain chronic inflammatory diseases, Kaposi's sarcoma, and cancer.

Antiangiogenesis Is Produced by Nontoxic Doses of Vinblastine

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4143-4155 ◽  
Author(s):  
Angelo Vacca ◽  
Monica Iurlaro ◽  
Domenico Ribatti ◽  
Monica Minischetti ◽  
Beatrice Nico ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Wide Spectrum ◽  
Chorioallantoic Membrane ◽  
Ultrastructural Level ◽  
Matrix Metalloproteinase 2 ◽  
Cell Functions ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract The effects of vinblastine (VBL) on endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, spreading on fibronectin (FN), secretion of matrix-metalloproteinase-2 (MMP-2) and MMP-9, and morphogenesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. In vitro, at noncytotoxic doses (0.1, 0.25, 0.5, 0.75, and 1 pmol/L), VBL impacted all these functions, except secretion of MMPs, in a dose-dependent fashion. By contrast, proliferation of other primary cells such as fibroblasts and lymphoid tumor cells was not impacted. In vivo, VBL at 0.5, 0.75, and 1 pmol/L again displayed a dose-dependent antiangiogenic activity. Lack of cytotoxicity in vitro and in vivo was shown both morphologically, and also because the antiangiogenic effects were rapidly abolished when VBL was removed. Apoptosis was not induced. At the ultrastructural level, impairment of cell functions in vitro was associated with thin disturbance of the cytoskeleton, in the form of slight depolymerization and accumulation of microfilaments, which was equally reversible. Results suggest that VBL has an antiangiogenic component at very low, noncytotoxic doses, and that antiangiogenesis by VBL could be used to treat a wide spectrum of angiogenesis-dependent diseases, including certain chronic inflammatory diseases, Kaposi's sarcoma, and cancer.

Bortezomib Targets Multiple Myeloma Endothelial Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4903-4903
Author(s):  
Aldo M. Roccaro ◽  
Teru Hideshima ◽  
Noopur Raje ◽  
Shaji Kumar ◽  
Kenji Ishitsuka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cells ◽  
Chorioallantoic Membrane ◽  
High Dose ◽  
Thymidine Uptake ◽  
Similar Data ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract Introduction: Bone marrow (BM) angiogenesis is an important hallmark of multiple myeloma (MM) which correlates with progression. Although MM remains incurable despite conventional and high-dose chemotherapy, the proteasome inhibitor Bortezomib (Velcade, formerly PS-341), can overcome conventional drug resistance in vitro and in vivo and it has recently been FDA approved for treatment of relapsed and refractory multiple myeloma. Here we evaluated whether anti-angiogenesis may contribute to the anti-MM activity of PS-341. We examined the effect of PS-341 on the angiogenic phenotype of endothelial cells (ECs) isolated from BM of patients with MM. Methods: MMECs were extracted from BM of patients with active MM using a lectin-based method. The MMEC population contained >95% factor VIII-related antigen (FVIII-RA)+ and CD31+ cells, as assessed by fluorescence activated cell sorting (FACS). Contamination by macrophages and plasma cells was <5%, evaluated by FACS for CD14 and CD38 positivity, respectively, as well as by RT-PCR and Western blot for CD38. Viability, assessed by trypan blue was >90%. MTT assay and [3H] thymidine uptake were used to evaluate the effects of PS-341 on survival and proliferation, respectively, of MMECs. Proliferation of MM.1S cells cocoltured with MMECs was measured by [3H] thymidine uptake. Cytokine (IL-6, VEGF) levels were quantitated by ELISA. Other in vitro angiogenesis functions examined included chemotaxis, spreading on fibronectin (FN), and morphogenesis on Matrigel. Ongoing work is looking at the effect of PS-341 on angiogenesis in vivo by using a chick embryo chorioallantoic membrane (CAM) model. Results: PS-341, at concentrations achievable in the plasma of patients, inhibited in vitro MMEC and HUVEC functions related to angiogenesis, including proliferation, chemotaxis, spreading on FN, and capillary formation on Matrigel. All these functions were affected in a dose-dependent fashion. A significant concentration-dependent reduction of VEGF and IL-6 production was observed in the presence of PS-341, as demonstrated by ELISA. Importantly, binding of MM.1S cells to MMECs triggers tumor cell proliferation, and PS-341 inhibits proliferation of adherent MM.1S cells in a dose-dependent fashion. Similar data were demonstrated in HUVECs. Conclusions: These data therefore demonstrate that PS-341 acts both directly and indirectly against MMECs, another mechanism which may contribute to the anti-MM activity of PS-341.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4039-4045
Author(s):  
Giovanni Bernardini ◽  
Gaia Spinetti ◽  
Domenico Ribatti ◽  
Grazia Camarda ◽  
Lucia Morbidelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Rnase Protection Assay ◽  
Chorioallantoic Membrane ◽  
Rnase Protection ◽  
Cc Chemokine ◽  
Cell Functions

Several chemokines have been shown to act as angiogenic molecules or to modulate the activity of growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF). The detection of the CC chemokine receptor (CCR) 8 message in human umbilical vein endothelial cells (HUVECs) by reverse transcription– polymerase chain reaction (RT-PCR) and RNase protection assay (RPA), prompted us to investigate the potential role exerted by the CC chemokine I-309, a known ligand of such receptor, in both in vitro and in vivo angiogenesis assays. We show here that I-309 binds to endothelial cells, stimulates chemotaxis and invasion of these cells, and enhances HUVEC differentiation into capillary-like structures in an in vitro Matrigel assay. Furthermore, I-309 is an inducer of angiogenesis in vivo in both the rabbit cornea and the chick chorioallantoic membrane assay (CAM).

Human Erythropoietin Induces a Pro-Angiogenic Phenotype in Cultured Endothelial Cells and Stimulates Neovascularization In Vivo

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2627-2636 ◽  
Author(s):  
Domenico Ribatti ◽  
Marco Presta ◽  
Angelo Vacca ◽  
Roberto Ria ◽  
Roberta Giuliani ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Chorioallantoic Membrane ◽  
Janus Kinase ◽  
Angiogenic Factor ◽  
Matrix Metalloproteinase 2 ◽  
Angiogenic Potential ◽  
Angiogenic Response

Abstract Hematopoietic and endothelial cell lineages share common progenitors. Accordingly, cytokines formerly thought to be specific for the hematopoietic system have been shown to affect several functions in endothelial cells, including angiogenesis. In this study, we investigated the angiogenic potential of erythropoietin (Epo), the main hormone regulating proliferation, differentiation, and survival of erythroid cells. Epo receptors (EpoRs) have been identified in the human EA.hy926 endothelial cell line by Western blot analysis. Also, recombinant human Epo (rHuEpo) stimulates Janus Kinase-2 (JAK-2) phosphorylation, cell proliferation, and matrix metalloproteinase-2 (MMP-2) production in EA.hy926 cells and significantly enhances their differentiation into vascular structures when seeded on Matrigel. In vivo, rHuEpo induces a potent angiogenic response in the chick embryo chorioallantoic membrane (CAM). Accordingly, endothelial cells of the CAM vasculature express EpoRs, as shown by immunostaining with an anti-EpoR antibody. The angiogenic response of CAM blood vessels to rHuEpo was comparable to that elicited by the prototypic angiogenic cytokine basic fibroblast growth factor (FGF2), it occurred in the absence of a significant mononuclear cell infiltrate, and it was not mimicked by endothelin-1 (ET-1) treatment. Taken together, these data demonstrate the ability of Epo to interact directly with endothelial cells and to elicit an angiogenic response in vitro and in vivo and thus act as a bona fide direct angiogenic factor.

scholarly journals Korean Red Ginseng Suppresses Metastasis of Human Hepatoma SK-Hep1 Cells by Inhibiting Matrix Metalloproteinase-2/-9 and Urokinase Plasminogen Activator

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yu-Ling Ho ◽  
Kun-Cheng Li ◽  
Wei Chao ◽  
Yuan-Shiun Chang ◽  
Guan-Jhong Huang
Keyword(s):  
Wide Spectrum ◽  
Water Extract ◽  
Inhibitory Effect ◽  
Matrix Metalloproteinase 2 ◽  
Boyden Chamber ◽  
Human Hepatoma ◽  
Red Ginseng ◽  
Korean Red Ginseng ◽  
Dose Dependent

Korean red ginseng and ginsenosides have been claimed to possess wide spectrum of medicinal effects, of which anticancer effect is one. The present study was undertaken to investigate the antimetastatic effect of Korean red ginseng on human hepatoma as well as possible mechanisms. The inhibitory effect of the water extract of Korean red ginseng (WKRG) on the invasion and motility of SK-Hep1 cells was evaluated by the Boyden chamber assayin vitro. Without causing cytotoxicity, WKRG exerted a dose-dependent inhibitory effect on the invasion and motility, but not adhesion, of highly metastatic SK-Hep1 cells. Zymography analyses revealed significant downregulating effects on MMP-2, MMP-9, and uPA activities in SK-Hep1 cells. Western blot analyses also showed that WKRG treatment caused dose-dependent decreases in MMP-2 and MMP-9 protein expressions. Moreover, WKRG increased the levels of TIMP-1, TIMP-2, and PAI-1. The present study not only demonstrated that invasion and motility of cancer cells were inhibited by WKRG, but also indicated that such effects were likely associated with the decrease in MMP-2/-9 and uPA expressions of SK-Hep1 cells.

scholarly journals Cloned LYT-2+ cytolytic T lymphocytes destroy allogeneic tissue in vivo.

1984 ◽  
Vol 159 (1) ◽  
pp. 234-243 ◽  
Author(s):  
J D Tyler ◽  
S J Galli ◽  
M E Snider ◽  
A M Dvorak ◽  
D Steinmuller
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytolytic T Lymphocytes ◽  
Transplantation Immunity ◽  
Dose Dependent Fashion ◽  
Dose Dependent

The long-accepted notion that alloimmune cytolytic T cells (CTL) mediate transplantation immunity has recently been called into question. In order to ascertain directly whether alloimmune CTL can mediate destruction of foreign tissue, we tested the ability of mouse CTL expanded as cloned populations in vitro to destroy allogeneic skin in vivo. The results of these studies prove unequivocally that cloned Lyt-2+ CTL can perform this task in an immunologically specific, H-2-restricted, and dose-dependent fashion.

scholarly journals Extracellular Nanovesicles Secreted by Human Osteosarcoma Cells Promote Angiogenesis

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 779 ◽  
Author(s):  
Francesca Perut ◽  
Laura Roncuzzi ◽  
Nicoletta Zini ◽  
Annamaria Massa ◽  
Nicola Baldini
Keyword(s):  
Endothelial Cell ◽  
Chorioallantoic Membrane ◽  
Tube Formation ◽  
Osteosarcoma Cells ◽  
Cell Functions ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Neutral Conditions

Angiogenesis involves a number of different players among which extracellular nanovesicles (EVs) have recently been proposed as an efficient cargo of pro-angiogenic mediators. Angiogenesis plays a key role in osteosarcoma (OS) development and progression. Acidity is a hallmark of malignancy in a variety of cancers, including sarcomas, as a result of an increased energetic metabolism. The aim of this study was to investigate the role of EVs derived from osteosarcoma cells on angiogenesis and whether extracellular acidity, generated by tumor metabolism, could influence EVs activity. For this purpose, we purified and characterized EVs from OS cells maintained at either acidic or neutral pH. The ability of EVs to induce angiogenesis was assessed in vitro by endothelial cell tube formation and in vivo using chicken chorioallantoic membrane. Our findings demonstrated that EVs derived from osteosarcoma cells maintained either in acidic or neutral conditions induced angiogenesis. The results showed that miRNA and protein content of EVs cargo are correlated with pro-angiogenic activity and this activity is increased by the acidity of tumor microenvironment. This study provides evidence that EVs released by human osteosarcoma cells act as carriers of active angiogenic stimuli that are able to promote endothelial cell functions relevant to angiogenesis.

I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4039-4045 ◽  
Author(s):  
Giovanni Bernardini ◽  
Gaia Spinetti ◽  
Domenico Ribatti ◽  
Grazia Camarda ◽  
Lucia Morbidelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Rnase Protection Assay ◽  
Chorioallantoic Membrane ◽  
Rnase Protection ◽  
Cc Chemokine ◽  
Cell Functions

Abstract Several chemokines have been shown to act as angiogenic molecules or to modulate the activity of growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF). The detection of the CC chemokine receptor (CCR) 8 message in human umbilical vein endothelial cells (HUVECs) by reverse transcription– polymerase chain reaction (RT-PCR) and RNase protection assay (RPA), prompted us to investigate the potential role exerted by the CC chemokine I-309, a known ligand of such receptor, in both in vitro and in vivo angiogenesis assays. We show here that I-309 binds to endothelial cells, stimulates chemotaxis and invasion of these cells, and enhances HUVEC differentiation into capillary-like structures in an in vitro Matrigel assay. Furthermore, I-309 is an inducer of angiogenesis in vivo in both the rabbit cornea and the chick chorioallantoic membrane assay (CAM).

scholarly journals Effect of Platelet-activating Factor onin vitroandin vivoInterleukin-6 Production

1994 ◽  
Vol 3 (4) ◽  
pp. 281-285 ◽  
Author(s):  
B. Pignol ◽  
T. Maisonnet ◽  
P. Guinot ◽  
J. M. Mencia-Huertac ◽  
P. Braquet
Keyword(s):  
Platelet Activating Factor ◽  
Similar Extent ◽  
Rat Serum ◽  
Mouse Fibroblasts ◽  
Dose Dependent Fashion ◽  
The One ◽  
Dose Dependent ◽  
Peak Increase

The aim of the present study was to investigate the possible effect of platelet-activating factor (PAF), by comparison with interleukin-1β and polyriboinositic/polyribocytidylic (poly I–C) acid, on IL-6 production by L 929 mouse fibroblasts. At concentrations above 1 μM PAF, the production of IL-6 by mouse fibroblasts was enhanced in a dose dependent fashion. At 5 μM PAF, the peak increase (60.1 ± 19.4 U/ml) was similar to that induced by 50 μg/ml poly I–C (60.0 ± 35.0 U/ml) and higher than the one evoked by 100 U/ml IL-1β (3.8 ± 1.8 U/ml). The increase of 11-6 activity induced by 5 μM PAF was maximal after a 22 h incubation period with L 929 cells. Lyso-PAF (5 μM) also increased IL-6 activity from fibroblasts to a similar extent compared with 5 μM PAF. In addition, the IL-6 activity induced by 5 μM PAF was still observed when the specific PAF antagonist, BN 52021 (10 μM), was added to the incubation medium of L 929 cells. The result suggests that the production of IL-6 by L 929 cells evoked by PAFin vitrois not receptor mediated. Thein vivoeffect of PAF on IL-6 production was also investigated in the rat. Two hours after intravenous injection of PAF (2 to 4 μg/kg), a dramatic increase of IL-6 activity in rat serum was observed, this effect being dose dependent. The increase of IL-6 induced by 3 μg/kg PAF was not observed when the animals were treated with the PAF antagonist, BN 52021 (1 to 60 mg/kg0. These results demonstrate that PAF modulates IL-6 production and that thein vivoeffect is receptor mediated.

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