scholarly journals Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 787 ◽  
Author(s):  
Rosalba D’Alessandro ◽  
Maria Grazia Refolo ◽  
Palma Aurelia Iacovazzi ◽  
Pasqua Letizia Pesole ◽  
Caterina Messa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Growth Factor Receptor ◽  
Annexin V ◽  
Therapeutic Effects ◽  
Experimental Conditions ◽  
Cell Growth And Migration ◽  
Low Concentrations ◽  
And Migration ◽  
Endothelial Growth Factor

Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell cycle analysis were assessed for cell proliferation and Annexin V and western blotting analysis relative to the expression of cleaved Caspase-3 and BID for cell apoptosis. In these experimental conditions cell growth and migration were potently inhibited and apoptosis induced even in HCC cells producing high alpha fetoprotein (AFP) levels (clinically worse prognosis). The combination also inhibited levels of the two HCC biomarkers, AFP and des gamma carboxy prothrombin (DCP). Additional inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced effects on AFP and DCP levels, cell growth inhibition and MAPK and PI3K/Akt signaling inhibition due to sorafenib/regorafenib combination. These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies.

scholarly journals Dual clathrin and adhesion signaling systems regulate growth factor receptor activation

2020 ◽  
Author(s):  
Marco A. Alfonzo-Mendez ◽  
Kem A. Sochacki ◽  
Marie-Paule Strub ◽  
Justin W. Taraska
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Growth Factor Signaling ◽  
Cell Growth And Migration ◽  
Reciprocal Regulation ◽  
Signaling Systems ◽  
Fluorescence And Electron Microscopy ◽  
And Migration

ABSTRACTThe crosstalk between growth factor and adhesion receptors is key for cell growth and migration. In pathological settings, these receptors are drivers of cancer. Yet, how growth and adhesion signals are spatially organized and integrated is poorly understood. Here we use quantitative fluorescence and electron microscopy to reveal a mechanism where flat clathrin lattices partition and activate growth factor signals via a coordinated response that involves crosstalk between epidermal growth factor receptor (EGFR) and the adhesion receptor β5-integrin. We show that ligand-activated EGFR, Grb2, Src, and β5-integrin are captured by clathrin coated-structures at the plasma membrane. Clathrin structures dramatically grow in response to ligand activation into large flat plaques and provide a signaling platform that link EGFR and β5-integrin through Src-mediated phosphorylation. Disrupting this EGFR/Src/β5-integrin axis prevents both clathrin plaque growth and receptor signaling. Our study reveals a reciprocal regulation of clathrin lattices and two different receptor systems to enhance cell growth factor signaling. These findings have broad implications for the control of growth factor receptors, mechanotransduction, and endocytosis.

scholarly journals Ramucirumab – egy új gyógyszer az onkológiában

2016 ◽  
Vol 157 (40) ◽  
pp. 1587-1594 ◽  
Author(s):  
András Telekes ◽  
Dániel Deme
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Local Relapse ◽  
Vascular Endothelial ◽  
Previously Treated ◽  
And Migration ◽  
Endothelial Growth Factor

Ramucirumab is a humanized monoclonal antibody against vascular endothelial growth factor receptor-2, which inhibits the binding of vascular endothelial growth factor-A, -C and -D ligands. Furthermore it blocks the ligand stimulated activation of p44/p42 mitogen activated protein kinases, thus neutralizing the ligand induced proliferation and migration of human endothelial cells. Based on the results of the REGARD (Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma) and the RAINBOW (Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma) studies ramucirumab was approved for 2nd line treatment as monotherapy and in combination with paclitaxel for patients with local relapse and unresectable or metastatic gastric cancer (including gastro-esophegal junction adenocarcinoma). Based on the results, in advanced solid malignancies, ramucirumab may prolong progression free survival and overall survival, although it may increase the risk of all adverse events (fatigue, neutropenia, haemorrhage, nausea, stomatitis). The authors review the clinical studies of ramucirumab. Orv. Hetil., 2016, 157(40), 1587–1594.

scholarly journals A Comprehensive Assessment of Apigenin as an Antiproliferative, Proapoptotic, Antiangiogenic and Immunomodulatory Phytocompound

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 858 ◽  
Author(s):  
Alexandra Ghițu ◽  
Anja Schwiebs ◽  
Heinfried H. Radeke ◽  
Stefana Avram ◽  
Istvan Zupko ◽  
...  
Keyword(s):  
Comprehensive Evaluation ◽  
Annexin V ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Cell Growth And Migration ◽  
Atp Production ◽  
Lactate Dehydrogenase Release ◽  
High Concentrations ◽  
And Migration ◽  
Lps Activation

Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.

Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 428-435 ◽  
Author(s):  
Klaus Podar ◽  
Yu-Tzu Tai ◽  
Faith E. Davies ◽  
Suzanne Lentzsch ◽  
Martin Sattler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Myeloma Cell ◽  
Signaling Cascades ◽  
Vascular Endothelial ◽  
Cell Growth And Migration ◽  
And Migration ◽  
Endothelial Growth Factor

Multiple myeloma (MM) remains incurable, with a median survival of 3 to 4 years. This study shows direct effects of vascular endothelial growth factor (VEGF) upon MM and plasma cell leukemia (PCL) cells. The results indicate that VEGF triggers tumor cell proliferation via a protein kinase C (PKC)–independent Raf-1–MEK–extracellular signal-regulated protein kinase pathway, and migration via a PKC-dependent pathway. These observations provide the framework for novel therapeutic strategies targeting VEGF signaling cascades in MM.

scholarly journals Anti-cancer effects of F16: A novel vascular endothelial growth factor receptor–specific inhibitor

Tumor Biology ◽  
2017 ◽  
Vol 39 (11) ◽  
pp. 101042831772684 ◽  
Author(s):  
Appu Rathinavelu ◽  
Khalid Alhazzani ◽  
Sivanesan Dhandayuthapani ◽  
Thanigaivelan Kanagasabai
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Growth ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Vascular Endothelial ◽  
And Migration ◽  
Endothelial Growth Factor

Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancers. This study was aimed to explore the anti-angiogenic activity of a novel vascular endothelial growth factor receptor–specific inhibitor named F16 in both in vitro and in vivo experimental models. This compound effectively reduced cell proliferation, tube formation, and migration of human umbilical vein endothelial cells in a concentration-dependent manner by directly inhibiting vascular endothelial growth factor binding and subsequent vascular endothelial growth factor receptor-2 phosphorylation. The F16 was also able to inhibit the phosphoinositide 3-kinase/protein kinase B–mediated survival and migration pathways in cancer in addition to inhibiting the focal adhesion kinase and mitogen-activated protein kinases–mediated signaling in GI-101A cancer cells. The chorioallantoic membrane assay followed by tumor growth inhibition measurements with GI-101A breast cancer xenograft implanted athymic nude mice confirmed the in vivo tumor reductive effects of F16. It was interesting to observe a decrease in tumor burden after F16 treatment which correlated very well with the decrease in the plasma levels of mucin-1 (MUC-1). Our studies so far have confirmed that F16 is a specific inhibitor of angiogenesis in both in vitro and in vivo models. The F16 also works very efficiently with Taxol in combination by limiting the tumor growth that is better than the monotherapy with any one of the drugs that were tested individually. Thus, F16 offers a promising anti-proliferative and anti-angiogenic effects with better specificity than some of the existing multi-kinase inhibitors.

scholarly journals A Peptide Antagonist of the ErbB1 Receptor Inhibits Receptor Activation, Tumor Cell Growth and Migration In Vitro and Xenograft Tumor Growth In Vivo

2010 ◽  
Vol 32 (4) ◽  
pp. 259-274
Author(s):  
Ruodan Xu ◽  
Gro Klitgaard Povlsen ◽  
Vladislav Soroka ◽  
Elisabeth Bock ◽  
Vladimir Berezin
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Epidermal Growth Factor ◽  
Tumor Cell ◽  
Erbb Receptors ◽  
Erbb Receptor ◽  
Cell Growth And Migration ◽  
Epidermal Growth ◽  
And Migration

The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in tumorigenesis and cancer disease progression, and therefore has become an attractive target for structure-based drug design. ErbB receptors are activated by ligand-induced homo- and heterodimerization. Structural studies have revealed that ErbB receptor dimers are stabilized by receptor–receptor interactions, primarily mediated by a region in the second extracellular domain, termed the “dimerization arm”. The present study is the first biological characterization of a peptide, termed Inherbin3, which constitutes part of the dimerization arm of ErbB3. Inherbin3 binds to the extracellular domains of all four ErbB receptors, with the lowest peptide binding affinity for ErbB4. Inherbin3 functions as an antagonist of epidermal growth factor (EGF)-ErbB1 signaling. We show that Inherbin3 inhibits EGF-induced ErbB1 phosphorylation, cell growth, and migration in two human tumor cell lines, A549 and HN5, expressing moderate and high ErbB1 levels, respectively. Furthermore, we show that Inherbin3 inhibits tumor growth in vivo and induces apoptosis in a tumor xenograft model employing the human non-small cell lung cancer cell line A549. The Inherbin3 peptide may be a useful tool for investigating the mechanisms of ErbB receptor homo- and heterodimerization. Moreover, the here described biological effects of Inherbin3 suggest that peptide-based targeting of ErbB receptor dimerization is a promising anti-cancer therapeutic strategy.

scholarly journals SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

2021 ◽  
Vol 9 ◽  
Author(s):  
Maxim L. Bychkov ◽  
Mikhail A. Shulepko ◽  
Olga V. Shlepova ◽  
Dmitrii S. Kulbatskii ◽  
Irina A. Chulina ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Growth ◽  
A549 Cell ◽  
Synthetic Peptide ◽  
A549 Cells ◽  
Growth Factor Receptor ◽  
Cancer Cell Growth ◽  
Α7 Nachr ◽  
And Migration

Secreted Ly6/uPAR-related protein 1 (SLURP-1) is a secreted Ly6/uPAR protein that negatively modulates the nicotinic acetylcholine receptor of α7 type (α7-nAChR), participating in control of cancer cell growth. Previously we showed, that a recombinant analogue of human SLURP-1 (rSLURP-1) diminishes the lung adenocarcinoma A549 cell proliferation and abolishes the nicotine-induced growth stimulation. Here, using multiplex immunoassay, we demonstrated a decrease in PTEN and mammalian target of rapamycin (mTOR) kinase phosphorylation in A549 cells upon the rSLURP-1 treatment pointing on down-regulation of the PI3K/AKT/mTOR signaling pathway. Decreased phosphorylation of the platelet-derived growth factor receptor type β (PDGFRβ) and arrest of the A549 cell cycle in the S and G2/M phases without apoptosis induction was also observed. Using a scratch migration assay, inhibition of A549 cell migration under the rSLURP-1 treatment was found. Affinity extraction demonstrated that rSLURP-1 in A549 cells forms a complex not only with α7-nAChR, but also with PDGFRα and epidermal growth factor receptor (EGFR), which are known to be involved in regulation of cancer cell growth and migration and are able to form a heterodimer. Knock-down of the genes encoding α7-nAChR, PDGFRα, and EGFR confirmed the involvement of these receptors in the anti-migration effect of SLURP-1. Thus, SLURP-1 can target the α7-nAChR complexes with PDGFRα and EGFR in the membrane of epithelial cells. Using chimeric proteins with grafted SLURP-1 loops we demonstrated that loop I is the principal active site responsible for the SLURP-1 interaction with α7-nAChR and its antiproliferative effect. Synthetic peptide mimicking the loop I cyclized by a disulfide bond inhibited ACh-evoked current at α7-nAChR, as well as A549 cell proliferation and migration. This synthetic peptide represents a promising prototype of new antitumor drug with the properties close to that of the native SLURP-1 protein.

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