scholarly journals Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
David E. Joyner ◽  
Kevin B. Jones ◽  
Stephen L. Lessnick ◽  
Joshua D. Schiffman ◽  
R. Lor Randall
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Fas Ligand ◽  
Death Domain ◽  
Apoptotic Pathway ◽  
Viable Cells ◽  
Therapeutic Mechanism ◽  
Epidermal Growth ◽  
Fas Pathway

One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL). The death-inducing signaling Ccmplex (DISC) and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor andin vitrodata suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas.

Effect of epidermal growth factor on secondary palatal epithelium in vitro: tissue isolation and recombination studies

Development ◽  
1980 ◽  
Vol 58 (1) ◽  
pp. 93-106
Author(s):  
Mary S. Tyler ◽  
Robert M. Pratt
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Programmed Cell Death ◽  
Dna Synthesis ◽  
Thymidine Incorporation ◽  
Control Medium ◽  
Epidermal Growth ◽  
Stimulation Of

Previous studies have shown that epidermal growth factor (EGF), a peptide of m.w. 6045, can specifically inhibit in organ culture the cessation of DNA synthesis and programmed cell death that normally occur in the presumptive fusion zone (PFZ) of the secondary palatal epithelium. The aim of this study was to determine if EGF acts directly on the epithelium to exert its effect and if there is a requirement for the underlying mesenchyme. Palatal processes from 13- and 14-day Swiss Webster embryonic mice were enzymatically separated into epithelium and mesenchyme which were then cultured alone or in transfilter recombination for up to 72 h. Tissues were examined by transmission- and scanning-electron microscopy and DNA synthesis was monitored autoradiographically using [3H]thymidine incorporation. In isolated epithelium cultured in control medium, cell death occurred in the PFZ and DNA synthesis did not occur in the oral and nasal epithelial regions. EGF (20–50 ng/ml) did not prevent cell death in the PFZ and failed to stimulate DNA synthesis in the isolated epithelium; EGF, however, did have an effect on epithelial cell morphology. In the presence of mesenchyme and EGF, there was extensive proliferation in the entire epithelium and cell death within the PFZ was not evident. The results indicate that the stimulation of DNA synthesis in the palatal epithelium by EGF requires the presence of the underlying mesenchyme and that EFG alone is not sufficient to inhibit programmed cell death within the PFZ of the isolated palatal epithelium.

P-glycoprotein plays a drug-efflux–independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2897-2904 ◽  
Author(s):  
Monica Pallis ◽  
Nigel Russell
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Apoptotic Cell ◽  
Patient Specific ◽  
Apoptosis Resistance ◽  
Reversal Agent ◽  
Apoptotic Pathway ◽  
Psc 833 ◽  
P Glycoprotein

P-glycoprotein (pgp), which is the product of the MDR1(multidrug resistance-1) gene, has an established role as a mediator of cytotoxic drug resistance in acute myeloid leukemia (AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7-AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a significant increase in apoptosis in the presence of the pgp-specific antibody UIC2 (mean increase: 58%; range: 11%-95%; P < .05). Likewise, apoptosis in growth factor–deprived TF1 cells cultured for 30 hours increased 2.5-fold in the presence of 25 μg/mL UIC2. The pgp reversal agent PSC-833 (1 μmol/L) augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to a comparable degree in 6 pgp−ve samples. To determine whether the sphingomyelin-ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific IC30 (the concentration of daunorubicin that caused apoptotic cell death in 30% of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was significantly more effective at augmenting apoptosis in pgp−ve patient blasts (median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples (median: 7%; range: 0%-27%;P = .028). Cellular accumulation of exogenous SM was associated with apoptosis and also occurred in nonapoptotic patient cells treated with PSC-833. However, this effect was not seen following treatment with the UIC2 antibody. These results indicate that pgp is able to exert a protective effect on AML cell viability and that this is associated with a reduced effect of exogenous SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp independent mechanism to alter SM distribution and to augment apoptosis induced in AML cells by serum and growth factor withdrawal.

scholarly journals Mechanisms Responsible for Granzyme B–Independent Cytotoxicity

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4085-4091 ◽  
Author(s):  
Sujan Shresta ◽  
John H. Russell ◽  
Timothy J. Ley
Keyword(s):  
Cell Death ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Mixed Lymphocyte Reaction ◽  
Granzyme B ◽  
Rapid Induction ◽  
Fas Pathway ◽  
Deficient Mice ◽  
Dependent Mechanism

Abstract Using granzyme B–deficient mice obtained by gene targeting, we previously demonstrated that granzyme B is required for the rapid induction of apoptotic target cell death by cytotoxic T lymphocytes (CTLs); however, CTLs are also equipped with additional effector mechanisms. In the present study, we examined the mechanisms responsible for granzyme B–independent cytotoxicity using in vitro lytic assays with CTLs derived from mice deficient for both granzyme B and Fas ligand (FasL) (granzyme B−/− × gld/gld) or for perforin and FasL (perforin × gld/gld). Our results show that primary mixed lymphocyte reaction (MLR)-derived CTLs from granzyme B−/− × gld/gld mice induce apoptosis of allogeneic targets with less efficiency and a longer delay than CTLs deficient for granzyme B alone. The residual cytotoxicity in granzyme B−/− × gld/gld CTLs is primarily accounted for by a perforin-dependent mechanism, since perforin−/− × gld/gld CTLs have virtually no residual cytotoxic activity in our assays. Granzyme B–independent cytotoxicity is therefore partially accounted for by the Fas pathway and partially by another perforin-dependent mechanism.

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

2020 ◽  
Vol 20 (18) ◽  
pp. 1628-1639
Author(s):  
Sergi Gómez-Ganau ◽  
Josefa Castillo ◽  
Andrés Cervantes ◽  
Jesus Vicente de Julián-Ortiz ◽  
Rafael Gozalbes
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Affinity ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Epidermal Growth

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.

4-Hydroxyestradiol improves mouse embryo quality, epidermal growth factor-binding capability in vitro and implantation rates

2020 ◽  
Author(s):  
Nuria Hernández ◽  
Marta López-Morató ◽  
Mario J Perianes ◽  
Soledad Sánchez-Mateos ◽  
Vanessa Casas-Rua ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Embryo Quality ◽  
Culture Media ◽  
Embryo Implantation ◽  
In Vivo Models ◽  
Endometrial Cells ◽  
Epidermal Growth ◽  
Binding Capability

Abstract Embryo implantation in the uterus is a critical step to achieve success following ART. Despite favorable uterine conditions, a great number of good quality embryos fail to implant, often for reasons that are unknown. Hence, improving the implantation potential of embryos is a subject of great interest. 4-Hydroxyestradiol (4-OH-E2), a metabolic product of estradiol produced by endometrial cells, plays a key role in endometrial–embryonic interactions that are necessary for implantation. Nonetheless, the effects of 4-OH-E2 on embryos obtained in vitro have not been yet described. This study was designed to determine whether culture media enriched in 4-OH-E2 could improve the quality and implantation rate of embryos obtained in vitro, using both in vitro and in vivo models. We also analyzed its effects on the epidermal growth factor (EGF)-binding capability of the embryos. Our results showed that the presence of 4-OH-E2 in the culture media of embryos during the morula to blastocyst transition increases embryo quality and attachment to endometrial cells in vitro. 4-OH-E2 can also improve viable pregnancy rates of mouse embryos produced in vitro, reaching success rates that are similar to those from embryos obtained directly from the uterus. 4-OH-E2 improved the embryos’ ability to bind EGF, which could be responsible for the increased embryo implantation potential observed. Therefore, our results strongly suggest that 4-OH-E2 is a strong candidate molecule to supplement human IVF culture media in order to improve embryo implantation. However, further research is required before these findings can be translated with efficacy and safety to fertility clinics.

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